KR19990077164A - A novel substituted imidazole compound - Google Patents

Abstract

New 1,4,5-substituted imidazole compounds and compositions for the treatment as cytokine inhibitors

Description

A novel substituted imidazole compound.

Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are biological substances produced in various cells such as mononuclear cells or macrophages. IL-1 has been described as mediating a variety of biological activities that are thought to be important in other physiological abnormalities such as immune regulation and inflammation (see, for example, Dinarello et al., Rev. Infect. Disease, 6, 51 (1984)). A number of known biological activities of IL-1 include activation of T helper cells, induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, acute phase protein induction and inhibition of plasma iron concentration.

There are many disease states associated with worsening of (or causing) the disease due to excessive or uncontrolled IL-1 production. These diseases include rheumatoid arthritis, osteoarthritis, endotoxemia and / or toxic shock, endotoxin induced inflammatory response or other acute or chronic pulmonary inflammatory disease conditions such as inflammatory bowel disease; Tuberculosis, atherosclerosis, osteoarthritis, cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis. There is recent evidence that the activity of IL-1 is also associated with diabetes and pancreatic beta cells.

(Dinarello, J. Clinical Immunology, 5 (5), 287-297 (1985)) discloses biological activities attributable to IL-1. It should be noted that some of these effects have been explained by others as an indirect effect of IL-1.

Excessive or uncontrolled TNF production may be associated with rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other joint abnormalities; Septic shock, septic shock, gram negative sepsis, toxic shock, adult respiratory distress syndrome, brain malaria, chronic pulmonary inflammatory disease, silicosis, sarcoisosis, bone resorption disease, reperfusion injury, graft AIDS, ARC (AIDS-related complications), keloid formation, scarring, as well as AIDS, AIDS, AIDS, AIDS related complications, Inflammatory bowel disease, Crohn's disease, ulcerative colitis, or pyresis. ≪ Desc / Clms Page number 2 >

AIDS is caused by infection of T-lymphocytes by human immunodeficiency virus (HIV). At least three types or strains of HIV were identified: HIV-1, HIV-2 and HIV-3. As a result of HIV infection, T-cell mediated immunity is impaired, and the infected patient presents with severe opportunistic infections and / or abnormal new organisms. Activation of T lymphocytes is required for HIV to enter T lymphocytes. Other cells such as HIV-1 and HIV-2 infect T lymphocytes after activation of T cells, and the expression and / or replication of the viral proteins is mediated or maintained by the T cell activation. Once an activated T lymphocyte is infected by HIV, the T lymphocyte must remain active to allow expression of the HIV gene and / or replication of HIV. Monocain, specifically TNF, is involved in the expression and / or viral replication of activated T-cell mediated HIV proteins by acting to keep T lymphocytes active. Thus, inhibiting monocaine activity by inhibiting, for example, monocaine production, particularly TNF production, in HIV-infected patients may help to limit T cell maintenance to an active state, It reduces the progression of HIV infection in Korea, slowing down or eliminating the progression of immune dysfunction caused by HIV infection. Mononuclear cells, macrophages, and related cells, such as Cooper and glial cells, are also involved in the maintenance of HIV infection. Like T-cells, these cells are targets for viral replication, and the level of viral replication depends on the activity of these cells. Monocaine such as TNF has been shown to activate HIV replication in monocytes and / or macrophages (Poli et al., Proc. Natl. Acad. Sci., 87: 782-784 (1990) ), Thus inhibiting the production or activity of monocaines helps to limit the progression of HIV as described above for T-cells.

TNF also plays a variety of roles in other viral infections such as cytomegalovirus (CMV), influenza virus and herpes virus for similar reasons as described.

Interleukin-8 (IL-8) was the first identified and characterized chemotactic factor in 1987. IL-8 is produced in several types of cells, including mononuclear cells, fibroblasts, endothelial cells and keratinocytes. Production in endothelial cells is induced by IL-1, TNF or lipopolysaccharide (LPS). Human IL-8 has been shown to act on neutrophils of mice, guinea pigs, rats and rabbits. IL-8 is referred to by many different names such as neutrophil inducing / activating protein-1 (NAP-1), mononuclear cell induced neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF) and T-cell lymphocyte chemotactic factor.

IL-8 stimulates a number of functions in vitro. IL-8 has been found to be chemoattractant to neutrophils, T-lymphocytes and basophils. In addition, IL-8 not only induces histamine release from basophils in both normal and atopic patients, but also induces lysozyme-enzyme release and respiratory explosion from neutrophils. IL-8 has also been shown to increase surface expression of Mac-1 (CD11b / CD18) on neutrophils without de novo protein synthesis, which may increase neutrophil adhesion to vascular endothelial cells. Many diseases are characterized by massive infiltration of neutrophils. Compounds that inhibit the production of IL-8 in abnormal conditions associated with increased production of IL-8 (the cause of neutrophil chemotaxis as an inflammatory site) may be beneficial.

IL-1 and TNF affect numerous cells and tissues, and these cytokines as well as other leukocyte-derived cytokines are important and essential inflammatory mediators of a number of disease states and abnormalities. Inhibiting these cytokines is beneficial in controlling, reducing and alleviating the majority of the disease states.

There is still a need in the art for compounds capable of inhibiting cytokine-inhibiting anti-inflammatory compounds, i.e. cytokines such as IL-1, IL-6, IL-8 and TNF.

SUMMARY OF THE INVENTION [

The present invention relates to a pharmaceutical composition comprising a novel compound of general formula I and a compound of general formula I and a pharmaceutically acceptable diluent or carrier.

The present invention relates to a method of treating CSBP / RK / p38 kinase mediated diseases in such mammals, comprising administering an effective amount of a compound of general formula I to a mammal in need of treatment of a CSBP / RK / p38 kinase mediated disease .

The present invention also relates to a method for the inhibition of cytokines and the treatment of cytokine mediated diseases in mammals, comprising administering an effective amount of a compound of general formula I to a mammal in need thereof, the inhibition of cytokines and the treatment of cytokine mediated diseases.

More particularly, the present invention relates to a method of inhibiting the production of IL-1 in a mammal comprising administering an effective amount of a compound of general formula I to a mammal in need of inhibiting IL-1 production.

More specifically, the present invention relates to a method of inhibiting the production of IL-8 in a mammal comprising administering to a mammal in need of inhibiting the production of IL-8 an effective amount of a compound of general formula I.

More particularly, the present invention relates to a method of inhibiting the production of TNF in a mammal comprising administering to a mammal in need of inhibiting the production of TNF an effective amount of a compound of general formula I.

Accordingly, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof,

In this formula,

R ₁ is 4-pyridyl, pyrimidinyl, quinolyl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl, wherein the heteroaryl ring is optionally substituted with YR _a substituted, optionally C _1-4 alkyl, halogen, hydroxyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl, CH ₂ OR _12, amino, mono and di -C _{1 -6} alkyl substituted amino, or _{N (R 10) C (O} ) , and additionally substituted with independent substituents selected from R _b or NHR _a,

Y is oxygen or sulfur,

R ₄ is phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl, optionally substituted with one or two substituents each independently selected from 4-phenyl, 4-naphthyl 1-yl, 5-naphth-2-yl or 6-naphth-2-yl in the case of substituent, halogen, cyano, _{nitro, -C (Z) NR 7 R} 17, -C (Z) oR _{16, - (CR 10 R 20} ) v COR 12, -SR 5, -SOR 5, -OR 12, halo-substituted -C _1-4 alkyl, C _1-4 alkyl, -ZC (Z) R _{12, -NR 10 C (Z) R 16} , or _{- (CR 10 R 20) v} NR 10 R 20, and, in the case of the other substitution positions, halogen, _{cyano, -C (Z) NR 13 R} 14, -C _{(Z) OR 3, - (} CR 10 R 20) m "COR 3, -S (O) m R 3, -OR 3, halo-substituted -C _1-4 alkyl, -C _1-4 alkyl, (CR _{10 R 20) m "NR 10} C (Z) R 3, -NR 10 S (O) m'R 8, -NR 10 S (O) m'NR 7 R 17, -ZC (Z) R 3 or - (CR ₁₀ R ₂₀ ) m "NR ₁₃ R ₁₄ ,

v is 0, or an integer of 1 or 2,

m is 0, or an integer of 1 or 2,

m 'is an integer of 1 or 2,

m " is 0, an integer of 1 to 5,

R ₂ is - (C ₁₀ R ₂₀ ) _n OR ₉ , heterocyclyl, heterocyclyl C _1-10 alkyl, C _1-10 alkyl, halo substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-10 alkyl, C _5-7 cycloalkenyl, C _5-7 cycloalkenyl -C _1-10- alkyl, aryl , aryl C _1-10 alkyl, heteroaryl, heteroaryl, -C _{1-10 alkyl, (CR 10 R 20) n} OR 11, (CR 10 R 20) n S (O) m R 18, (CR 10 R 20 _{) n NHS (O) 2 R} 18, (CR 10 R 20) n NR 13 R 14, (CR 10 R 20) n NO 2, (CR 10 R 20) n CN, (CR 10 R 20) n 'SO _{2 R 18, (CR 10 R} 20) n S (O) m 'NR 13 R 14, (CR 10 R 20) n OC (Z) R 11, (CR 10 R 20) n C (Z) OR 11, _{(CR 10 R 20) n C} (Z) NR 13 R 14, (CR 10 R 20) n C (Z) NR 11 OR 9, (CR 10 R 20) n NR 10 C (Z) R 11, (CR _{10 R 20) n NR 10 C} (Z) NR 13 R 14, (CR 10 R 20) n N (OR 6) C (Z) NR 13 R 14, (CR 10 R 20) n N (OR 6) C _{(Z) R 11, (CR} 10 R 20) n C (= NOR 6) R 11, (CR 10 R 20) n NR 10 C (= NR 19) NR 13 NR 14, (CR 10 R 20) n OC (Z) NR ₁₃ R ₁₄ , (CR ₁₀ R ₂₀ ) _n NR _{1 0 C (Z) NR 13 R} 14, (CR 10 R 20) n NR 10 C (Z) OR 10, 5- (R 18) -1,2,4- oxa designed ol-3-yl or 4- ( R ₁₂ ) -5- (R ₁₈ R ₁₉ ) -4,5-dihydro-1,2,4-oxadiazol-3-yl wherein aryl, arylalkyl, heteroaryl, heteroarylalkyl, cyclo The alkyl, cycloalkylalkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted,

n is an integer of 1 to 10,

n 'is 0, an integer of 1 to 10,

Z is oxygen or sulfur,

R _a is aryl, aryl C _1-6 alkyl, heterocyclic, heterocyclyl C _1-6 alkyl, heteroaryl, heteroaryl C _1-6 alkyl, wherein each of these moieties may optionally be substituted,

R _b is hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, aryl, arylC _1-4 alkyl, heteroaryl, heteroarylC _1-4 alkyl, heterocyclyl, or heterocyclylC _1-4 Alkyl,

R ₃ is heterocyclyl, heterocyclyl C _1-10 alkyl or R ₈ ,

R ₅ is selected from the group consisting of hydrogen, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl or NR ₇ , wherein the -SR ₅ is -SNR ₇ R ₁₇ and -SOR ₅ is- R < ₁₇ &

R ₆ is selected from the group consisting of hydrogen, a pharmaceutically acceptable cation, C _1-10 alkyl, C _3-7 cycloalkyl, aryl, arylC _1-4 alkyl, heteroaryl, heteroarylC _1-4 alkyl, heterocyclic, Or C _1-10 alkanoyl,

R ₇ and R ₁₇ are each independently selected from hydrogen or C _1-4 alkyl or R ₇ and R ₁₇ together with the nitrogen to which they are attached form a 5-7 membered heterocyclic ring optionally containing oxygen , Sulfur or NR < _{15 &} gt ;, wherein the heteroatom

R ₈ is C _1-10 alkyl, halo substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl, aryl, aryl C _1-10 alkyl, heteroaryl, heteroaryl C _{1-10 alkyl, (CR 10 R 20) nOR} 11, (CR 10 R 20) nS (O) mR 18, (CR 10 R 20) nNHS (O) 2 R ₁₈ , (CR ₁₀ R ₂₀ ) nNR ₁₃ R ₁₄ wherein aryl, arylalkyl, heteroaryl, heteroarylalkyl may optionally be substituted,

R ₉ is hydrogen, -C (Z) R ₁₁ or optionally substituted C _1-10 alkyl, S (O) ₂ R ₁₈ , optionally substituted aryl or optionally substituted aryl-C _1-4 alkyl,

R ₁₀ and R ₂₀ are each independently selected from hydrogen or C _1-4 alkyl,

R ₁₁ is selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-7 cycloalkyl, heterocyclyl, heterocyclyl C _1-10 alkyl, aryl, aryl C _1-10 alkyl, heteroaryl or heteroaryl C _1-10 alkyl ego,

R < ₁₂ > is hydrogen or R < ₁₆ &

R ₁₃ and R ₁₄ are each independently selected from hydrogen or optionally substituted C _1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C _1-4 alkyl, or together with the nitrogen to which they are attached form a 5-7 membered Form a heterocyclic ring, which ring optionally additionally contains a heteroatom selected from oxygen, sulfur or NR ₉ ,

R ₁₅ is R ₁₀ or C (Z) -C _1-4 alkyl,

R ₁₆ is C _1-4 alkyl, halo-substituted -C _1-4 alkyl, or C _3-4 cycloalkyl,

R ₁₈ is C _1-10 alkyl, C _3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C _1-10 alkyl, heteroaryl or heteroarylalkyl,

R ₁₉ is hydrogen, cyano, C _1-4 alkyl, C _3-7 cycloalkyl or aryl.

The present invention relates to a novel substituted imidazole compound, a process for its preparation, its use in the treatment of cytokine mediated diseases and a pharmaceutical composition for its treatment.

In Formula I, suitable R ₁ moieties include 4-pyridyl, 4-pyrimidinyl, 4-quinolyl, 6-isoquinolinyl, 4-quinazolinyl, 1-imidazolyl, Include a zolyl ring, of which 4-pyridyl, 4-pyrimidinyl and 4-quinoline rings are preferred. More preferred is a 4-pyrimidinyl or 4-pyridyl moiety, most preferably a 4-pyrimidinyl ring.

The R ₁ moiety is substituted with _a YR _a group. Where Y is oxygen or sulfur, R _a is aryl, aryl C _1-6 alkyl, heterocyclic, heterocyclic C _1-6 alkyl, heteroaryl, or heteroaryl C _1-6 alkyl, R _a portion of each May optionally be substituted as described below.

When R < _{a >} is aryl, phenyl or naphthyl is preferred. When R < _a > is arylalkyl, benzyl or naphthylmethyl is preferred. When R _a is a heterocyclic or heterocyclic alkyl moiety, the heterocyclic moiety is preferably selected from the group consisting of pyrrolidinyl, piperidine, morpholino, tetrahydropyran, tetrahydrothiopyranyl, tetrahydrothiopyrasulfinyl , Tetrahydrothiopyrazolesulfonyl, pyrrolidinyl, indole, or piperonyl ring. Heterocyclic rings are described herein as containing an unsaturated group as in the tryptamine ring.

When R < _a > is a heteroaryl ring as described below, it is preferably a pyridine or tetrazole ring.

R < _a >, aryl, heterocyclic and heteroaryl rings optionally are substituted one or more times, preferably one to three times independently by halogen; C _1-4 alkyl such as methyl, ethyl, propyl, isopropyl or t-butyl; Halo-substituted alkyl, such as CF _3; Hydroxy; Hydroxy-substituted C _1-4 alkyl; C _1-4 alkoxy such as methoxy or ethoxy; C (O) OR ₁₁ , such as S (O) _m alkyl and S (O) _m aryl (where m is 0, 1 or 2), C (O) C _1-4 alkyl or C (O) OH moieties; -O- (CH ₂ ) _s -O-, such as C (O) R ₁₁ , -OC (O) R _c , ketal or dioxyalkylene bridge; Amino; Mono- and di-C _1-6 alkyl substituted amino, -N (R ₁₀ ) C (O) R _b ; _{-C (O) NR 10 R 20} ; Cyano, nitro, or an N-heterocyclyl ring wherein the ring is 5-7 membered, optionally containing an additional heteroatom selected from oxygen, sulfur or NR ₁₅ ; Aryl, such as phenyl; Optionally substituted arylalkyl such as benzyl or phenethyl; Aryloxy such as phenoxy, or arylalkyloxy such as benzyloxy.

R _b is suitably hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, aryl, aryl C _1-4 alkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclyl, or heterocyclyl C _1-4 alkyl moieties, all of which may be optionally substituted as described below.

R _c is suitably C _1-6 alkyl, C _3-7 cycloalkyl, aryl, arylC _1-4 alkyl, heteroaryl, heteroarylC _1-4 alkyl, heterocyclyl, or heterocyclylC _{1- 4} alkyl moieties, all of which may be optionally substituted as described below.

Suitable R _a groups include benzyl, halosubstituted benzyl, naphthylmethyl, phenyl, halosubstituted phenyl, aminocarbonylphenyl, alkylphenyl, cyanophenyl, alkylthiophenyl, hydroxyphenyl, alkoxyphenyl, phenoxyphenyl, benzyl Phenylphenyl, methylenedioxyphenyl, trifluoromethylphenyl, methylsulfonylphenyl, tetrazole, methyltetrazolyl, morpholinopropyl, piperonyl, piperidin-4-yl, 1- methylpiper Alkyl substituted piperidines such as pyridine, or alkyl substituted piperidines such as 2,2,6,6-tetramethylpiperidin-4-yl.

R ₁ groups are additionally C _1-4 alkyl, halo, OH, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl, CH ₂ OR _12, amino, mono-and di -C _1-6 alkyl substituted _{amino, N (R 10) C (} O) R b NHR a, or a ring is a 5 to 7 membered, optionally N- heterocyclic group which contain an additional heteroatom selected from oxygen, sulfur or NR ₁₅ It can be independently substituted one or more times by a cyclic ring.

Additional R _{1 When} any substituent is N (R ₁₀ ) C (O) R _b , R _b is preferably C _1-6 alkyl, preferably R ₁₀ is hydrogen. The R _b moiety, in particular the C _1-6 alkyl group, is preferably optionally substituted one to three times with a halogen, such as fluorine, as in trifluoromethyl or trifluoroethyl.

The preferred ring arrangement on the R ₁ substituted with YR _a on the 4-pyridyl derivative is the 2-position and the preferred ring arrangement on the 4-pyrimidinyl ring is also the 2-position.

Suitably R ₄ is phenyl, naphth-1-yl or naphth-2-yl, optionally substituted by one or two substituents, or heteroaryl. More preferably, R ₄ is a phenyl or naphthyl ring. When R ₄ is 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-moiety, suitable substituents for R ₄ are heteroaryl, Or two substituents and each of the substituents is independently selected and in the case of 4-phenyl, 4-naphthyl-1-yl, 5-naphth-2-yl or 6-naphth- Halogen, -SR ₅ , -SOR ₅ , -OR ₁₂ , CF ₃ , or - (CR ₁₀ R ₂₀ ) _v NR ₁₀ R ₂₀ , and in the case of other substitution positions for these rings, preferred substituents are _{-S (O) m R 3,} -OR 3, CF 3, (CR 10 R 20) m "NR 13 R 14, -NR 10 C (Z) R 3 and -NR ₁₀ S (O) _{m 'is} R _8. phenyl and naphth-1-yl in the 4-position, naphth-2-yl 5-position preferred substituents include halogen, especially fluoro and chloro on the, and, -SR ₅ and -SOR ₅ (Wherein R ₅ is preferably C _1-2 alkyl, more preferably methyl), and among them, Preferred substituents at the 3-position of the phenyl and naphth-1-yl rings are halogens, in particular fluoro and chloro; -OR ₃ , in particular C _{1 - 4} alkoxy; CF _3, amino, such as _{NR 10 R 20; NR 10 C} (Z) R 3, especially -NHCO (C _{1-10 alkyl); - NR 10 S (O} ) m 'R 8, especially NHSO ₂ ( C _1-10 alkyl), and -SR ₃ , and -SOR ₃ , wherein R ₃ is preferably C _1-2 alkyl, more preferably methyl. When the phenyl ring is disubstituted preferably fluoro and chloro, preferably di-and two independent halogen parts such as chloro, and more preferably 3,4 position -OR ₃ and -ZC (Z) R ₃ are both part 3 Position, and R < ₃ > may also comprise hydrogen.

Preferably the R < ₄ > moiety is an unsubstituted or substituted phenyl moiety. More preferably R ₄ is phenyl or phenyl substituted at the 4-position with fluoro and / or phenyl at 3-position with fluoro, chloro, C _1-4 alkoxy, methane-sulfonamido or acetamido, or R ₄ is independently phenyl at the 3,4-position to chloro or fluoro, more preferably chloro. Most preferably, R ₄ is 4-fluorophenyl.

In the general formula (Z), Z is oxygen or sulfur, preferably oxygen.

Suitably, R ₂ is - (C ₁₀ R ₂₀ ) _n OR ₉ , heterocyclyl, heterocyclyl C _1-10 alkyl, C _1-10 alkyl, halo substituted C _1-10 alkyl, C _2-10 C _1-6 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-10 alkyl, C _5-7 cycloalkenyl, C _5-7 cycloalkenyl C _1-10 alkyl, (CR ₁₀ R ₂₀ ) _n OR ₁₁ , (CR ₁₀ R ₂₀ ) _n S (O) _m R ₁₈ , (CR ₁₀ R ₂₀ ) _n R ₁₁ , aryl, arylC _1-10 alkyl, heteroaryl, heteroarylC _1-10 alkyl, _{) n NHS (O) 2 R} 18, (CR 10 R 20) n NR 13 R 14, (CR 10 R 20) n NO 2, (CR 10 R 20) n CN, (CR 10 R 20) n 'SO _{2 R 18, (CR 10 R} 20) n S (O) m 'NR 13 R 14, (CR 10 R 20) n C (Z) R 11, (CR 10 R 20) n OC (Z) R 11, _{(CR 10 R 20) n C} (Z) OR 11, (CR 10 R 20) n C (Z) NR 13 R 14, (CR 10 R 20) n C (Z) NR 11 OR 9, (CR 10 R _{20) n NR 10 C (Z} ) R 11, (CR 10 R 20) n NR 10 C (Z) NR 13 R 14, (CR 10 R 20) n N (OR 6) C (Z) NR 13 R 14 _{, (CR 10 R 20) n} n (OR 6) C (Z) R 11, (CR 10 R 20) n C (= NOR 6) R 11, (CR 10 R 20) n NR 10 C (= NR 19 ) NR ₁₃ NR ₁₄ , (CR ₁₀ R _{20 ) N OC (Z) NR 13} R 14, (CR 10 R 20) n NR 10 C (Z) NR 13 R 14, (CR 10 R 20) n NR 10 C (Z) OR 10, 5- (R 18 ) -1,2,4-oxa designed ol-3-yl or _{4- (R 12) -5- (R} 18 R 19) -4,5- dihydro-1,2,4-oxadiazol -3 -, wherein the cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic and heterocyclic alkyl moieties may be optionally substituted.

Suitably, n is an integer from 1 to 10, m is 0, or an integer of 1 or 2, n 'is 0, or an integer from 1 to 10, and m' is 1 or 2. Preferably, n is from 1 to 4.

Preferably R ₂ is an optionally substituted heterocyclyl ring, an optionally substituted heterocyclyl C _1-10 alkyl, an optionally substituted C _1-10 alkyl, an optionally substituted C _3-7 cycloalkyl, an optionally substituted C ₃ alkyl _-7 cycloalkyl C _{1-10 alkyl, (CR 10 R 20) n} C (Z) OR 11 _{group, (CR 10 R 20) n} NR 13 R 14, (CR 10 R 20) n NHS (O) 2 R ₁₈ , (CR ₁₀ R ₂₀ ) _n S (O) _m R ₁₈ , optionally substituted aryl; Optionally substituted aryl C _{1-10 alkyl, (CR 10 R 20) n} OR 11, (CR 10 R 20) n C (Z) R 11, or _{(CR 10 R 20) n C} (= NOR 6) R 11 .

More preferably, R ₂ is an optionally substituted heterocyclyl ring, optionally substituted heterocyclyl C _1-10 alkyl, optionally substituted aryl, optionally substituted C _3-7 cycloalkyl, optionally substituted C _3-7 cyclo alkyl C _{1-10 alkyl, (CR 10 R 20) n} NR 13 R 14, or _{(CR 10 R 20) n C} (Z) is an oR ₁₁ group.

When R ₂ is optionally substituted heterocyclyl, the ring is preferably a morpholino, pyrrolidinyl, or piperidinyl group. When the ring is optionally substituted, the substituent may be attached directly to the free nitrogen, such as in a piperidinyl group or a pyrrole ring, or to the ring itself. Preferably the ring is piperidine or pyrrole, more preferably piperidine. The heterocyclyl ring is independently 1-4 times halogen; C _1-4 alkyl; Aryl, such as phenyl; Such as benzyl, wherein the aryl or arylalkyl moiety itself may optionally be substituted with C (O) C _1-4 alkyl or C (O) OH moieties, such as in the definitions of C (O) OR ₁₁ ; C (O) H; C (O) C _1-4 alkyl, hydroxy substituted C _1-10 alkyl, C _1-10 alkoxy, S (O) _m C _1-4 alkyl, wherein m is 0, 1 or 2, NR ₁₀ R ₂₀ wherein R ₁₀ and R ₂₀ are independently hydrogen or C _1-4 alkyl.

Preferably, when the ring is piperidine, the ring is attached to the imidazole at the 4-position and the substituent is selected from the group consisting of the active nitrogen phase, 1-formyl-4-piperidine, 1-methyl-4-piperidine, 1-ethoxycarbonyl-4-piperidine. If the ring is substituted by an alkyl group, the ring is attached to the 4-position and is preferably substituted in the 2- or 6-position or both positions, such as 2,2,6,6-tetramethyl-4-piperidine . Likewise, when the ring is a pyrrole, the ring is attached to the imidazole at the 3-position and all of the substituents are directly on the active nitrogen.

When R ₂ is an optionally substituted heterocyclyl C _1-10 alkyl group, the ring is preferably a morpholino, pyrrolidinyl or piperidinyl group. Preferably, the alkyl moiety is 1 to 4, more preferably 3 or 4, and most preferably 3, such as a propyl group. Preferred heterocyclic alkyl groups include, but are not limited to, morpholinoethyl, morpholinopropyl, pyrrolidinylpropyl and piperidinylpropyl moieties. The heterocyclic ring herein is also optionally substituted in the same manner as the direct bond of said heterocyclyl.

When R ₂ is an optionally substituted C _3-7 cycloalkyl or optionally substituted C _3-7 cycloalkyl C _1-10 alkyl, the cycloalkyl group is preferably a C ₄ or C ₆ ring, and most preferably C ₆ Wherein the ring in the formula is optionally substituted. The cycloalkyl ring may optionally be substituted with a halogen such as fluorine, chlorine, bromine or iodine; Hydroxy; C _1-10 alkoxy such as methoxy or ethoxy; S (O) _m alkyl (wherein m is 0, 1 or 2) such as methylthio, methylsulfinyl or methylsulfonyl; S (O) _m aryl; NR ₇ R ₁₇ group wherein R ₇ and R ₁₇ are as defined in formula I or together with the nitrogen to which they are attached form a 5- to 7-membered ring optionally containing oxygen, sulfur or NR ₁₅ and R ₁₅ includes a heteroatom selected from equality as defined in formula I) _{additionally; N (R 10) C (} O) X 1 ( wherein, R ₁₀ is the same as defined in formula I, X ₁ is C _1-4 alkyl, aryl or aryl C _{1-4 alkyl); N (R 10) C} (O) aryl; C _1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl or t- ; substituents (such as CF _3), halogen, hydroxy, nitro, cyano, amino, NR ₇ R single and as in the _{17th-substituted} amino, S (O) _m alkyl and S (O) _m aryl (where m is 0, 1 or 2), optionally substituted alkylene such as ethylene or propylene, optionally substituted alkyne such as ethyne, and the like, such as the free acid or methyl ester derivative C (O) OR ₁₁ , wherein R ₁₁ is as defined in general formula I, R _e group, -C (O) H, = O, = N-OR _11, -N (H) alkyl or a aryl derivative substituted at the nitrogen or the oxime _{portion); -N (oR d) -C} (O) -R f; optionally substituted aryl, such as phenyl, such as benzyl of phenethyl, optionally substituted aryl C _{1 -4} alkyl, such as optionally substituted heterocyclyl, or heterocyclic C _1-4 alkyl, and more aryl, ahkil, heterocyclic and heterocyclic alkyl moiety is halogen, hydroxy, C _1-10 alkyloxy, Alkyl, halosubstituted alkyl, such as S (O) _m alkyl, cyano, nitro, amino, NR ₇ R ₁₇ groups.

Suitably R _d is hydrogen, a pharmaceutically acceptable cation, aroyl or a C _1-10 alkanoyl group.

Suitably, R _e is selected from the group consisting of 1,3-di (thiophene) -O- (CH ₂ ) _s -O- wherein s is 1 to 3, preferably s is 2 and produces a 1,3- An oxyalkylene group, or a ketal functional group.

Suitably R _f is NR ₂₁ R ₂₂ , alkyl _1-6 , halo substituted alkyl _1-6 , hydroxy substituted alkyl _1-6 , alkenyl _2-6 , halogen, alkyl _1-6 , halo substituted alkyl _1-6 , hydroxyl, or heteroaryl or aryl optionally substituted with alkoxy _1-6 .

Suitably R < ₂₁ > is hydrogen, or alkyl _1-6 .

Suitably, R ₂₂ is selected from the group consisting of hydrogen, alkyl _1-6 , aryl, benzyl, heteroaryl, halogen or hydroxy substituted by halo, cyano, alkyl _1-12 , alkoxy _1-6 , halo substituted alkyl _1-6, alkylthio, alkylsulfonyl, or phenyl substituted by a member selected from the group consisting of alkyl sulfinyl; Or R < ₂₁ > and R < ₂₂ > together with the nitrogen to which they are attached form a 5-7 membered ring, which member may be optionally substituted by a heteroatom selected from oxygen, sulfur or nitrogen. The rings may be saturated or contain one or more unsaturated bonds. Preferably R _f is NR ₂₁ R ₂₂ , more preferably R ₂₁ and R ₂₂ are both hydrogen.

When the R ₂ cycloalkyl moiety is substituted by an NR ₇ R ₁₇ group, or an NR ₇ R ₁₇ C _1-10 alkyl group and R ₇ and R ₁₇ are defined as in formula I, the substituent is preferably amino, amino Alkyl or an optionally substituted pyrrolidinyl moiety.

The preferred ring arrangement for the cycloalkyl moiety is the 4-position, as in the C ₆ ring. When the cycloalkyl ring is a di-substituent, it is preferably -substituted at the 4-position as follows.

Wherein R ^{1 '} and R ^2' are independently any of the substituents described for R ₂ above.

Preferably, R ^{1 'and} R ^2' is hydrogen, hydroxy, alkyl, substituted alkyl, an optionally substituted alkynyl, aryl, arylalkyl, NR ₇ R _17, and _{N (R 10) C (O} ) R 11 . Suitably alkyl is C _1-4 alkyl such as methyl, ethyl, or isopropyl; NR ₇ R ₁₇ and NR ₇ R ₁₇ alkyl such as amino, methylamino, aminomethyl, aminoethyl; Substituted alkyl such as cyano, methyl, cyano, ethyl, nitro, and pyrrolidinyl; Aryl, such as in phenyl; Arylalkyl such as in benzyl; Optionally substituted alkylene such as ethylene or propylene; Or R < ¹ & gt ^; and R < ² > together are keto functional.

When R ₂ is (CR ₁₀ R ₂₀ ) _n NR ₁₃ R ₁₄ and R ₁₃ and R ₁₄ are as defined in formula I, R ₁₃ and R ₁₄ are each independently hydrogen, optionally substituted C _1-4 alkyl , Optionally substituted aryl or optionally substituted aryl-C _1-4 alkyl, or nitrogen to which they are attached form a 5- to 5-membered heterocyclic ring optionally containing heteroatoms selected from oxygen, sulfur, or NR ₉ , And further contains an element. In some cases it has been found that it can also produce moieties such as the above heterocyclic C _1-10 alkyl moieties which are suitable R ₂ variables.

Preferably R ₁₃ and R ₁₄ are independently hydrogen, C _1-4 alkyl, preferably methyl or benzyl. n is preferably 1 to 4, more preferably 3 or 4, and most preferably 3, such as a propyl group. Preferred groups include, but are not limited to, aminopropyl, (N-methyl-N-benzyl) aminopropyl, (N-phenylmethyl) amino-1-propyl or diethylaminopropyl.

When R ₂ is (CR ₁₀ R ₂₀ ) _n C (Z) OR ₁₁ group, R ₁₁ is suitably hydrogen, C _1-4 alkyl, especially methyl. n is preferably 1 to 4, more preferably 2 or 3 as in the ethyl or propyl group. Preferred groups include, but are not limited to, carboxymethyl-1-butyl, carboxy-1-propyl, or 2-acetoxyethyl.

When R ₂ is (CR ₁₀ R ₂₀ ) _n S (O) _m R ₁₈ group, m is 0, 1 or 2 and R ₁₈ is preferably aryl, especially phenyl or C _1-10 alkyl, especially methyl. n is preferably 1 to 4, more preferably 2 or 3 as in the ethyl or propyl group.

When R ₂ is (CR ₁₀ R ₂₀ ) _n OR ₁₁ group, R ₁₁ is suitably hydrogen, aryl, especially phenyl or C _1-10 alkyl, especially methyl or ethyl. n is preferably 1 to 4, more preferably 2 or 3 as in the ethyl or propyl group.

When R ₂ is (CR ₁₀ R ₂₀ ) _n NHS (O) ₂ R ₁₈ group, R ₁₈ is suitably alkyl, especially methyl. n is preferably 1 to 4, more preferably 2 or 3 as in the ethyl or propyl group.

When R < _{2 >} is an optionally substituted aryl, the aryl is preferably phenyl. The aryl ring is preferably C _1-4 alkyl, halogen, especially fluoro or chloro, (CR ₁₀ R ₂₀ ) _t OR ₁₁ , (CR ₁₀ R ₂₀ ) _t NR ₁₀ R ₂₀ , in particular amino or mono- Amino, (CR ₁₀ R ₂₀ ) _t S (O) _m R ₁₈ wherein m is 0, 1 or 2; SH-, (CR ₁₀ R ₂₀ ) _n NR ₁₃ R ₁₄ , NR ₁₀ C (Z) R ₃ (NHCO (C _1-10 alkyl)); NR ₁₀ S (O) _m R ₈ (NHSO ₂ (C _1-10 alkyl)); t is 0 or an integer of 1 to 4;

When R ₂ is an optionally substituted heteroaryl or heteroarylalkyl group, the ring may be optionally substituted with C _1-4 alkyl, halogen, especially fluoro or chloro, (CR ₁₀ R ₂₀ ) _t OR ₁₁ , (CR ₁₀ R ₂₀ ) _t NR ₁₀ R ₂₀ , in particular amino or mono- or di-alkylamino- (CR ₁₀ R ₂₀ ) _t S (O) _m R ₁₈ wherein m is 0, 1 or 2; SH, (CR ₁₀ R ₂₀ ) _{n -NR 13 R 14, NR 10 C} (Z) R 3 (NHCO (C 1-10 _{alkyl); NR 10 S (O)} m R 8 (NHSO 2 (1 or more times independently selected by a C _1-10 alkyl) And may be optionally substituted one or more times, preferably by one or two substituents, and t is zero or an integer of from 1 to 4.

Those skilled in the art will appreciate that where R ₂ is (CR ₁₀ R ₂₀ ) _n OC (Z) R ₁₁ , or (CR ₁₀ R ₂₀ ) _n OC (Z) NR ₁₃ R ₁₄ moiety, , And a stable compound can be synthesized.

Preferably R ₂ is C _1-4 alkyl (branched and unbranched), especially methyl, methylthiopropyl, methylsulfinylpropyl, aminopropyl, N-methyl-N- benzylaminopropyl, diethylaminopropyl, Propylmethyl, morpholinylbutyl, morpholinylpropyl, morpholinylethyl, piperidine or substituted piperidine. More preferably R ₂ is selected from the group consisting of methyl, isopropyl, butyl, t-butyl, n-propyl, methylthiopropyl or methylsulfinylpropyl, morpholino propyl, morpholinyl butyl, hydrogen substituted phenyl, Sulfinylalkyl such as methylthio, methylsulfinyl, or methylsulfonyl moiety; Piperidinyl, 1-formyl-4-piperidine, 1-benzyl-4-piperidine, 1-methyl-4-piperidine or 1-ethoxycarbonyl-4-piperidine.

All of the present embodiment that the alkenyl or alkynyl part of a substituent group present an unsaturated bond in the example, that is, the vinylene or acetylene bonds are preferably nitrogen, oxygen or sulfur portion, for example, as in OR _3, or a constant R ₂ moiety.

The term " optionally substituted " as used herein, unless otherwise defined herein, includes halogens such as fluorine, chlorine, bromine or iodine; Hydroxy; Hydroxy substituted C _1-10 alkyl; C _1-10 alkoxy, such as methoxy or ethoxy; S (O) malkyl (wherein m is 0, 1 or 2) such as methylthio, methylsulfinyl or methylsulfonyl; Amino, mono- and di-substituted amino {e.g., NR ₇ R ₁₇ groups wherein R ₇ and R ₁₇ may be cyclized with the nitrogen to which they are attached to form a 5- to 7-membered ring, Wherein the ring optionally includes an additional heteroatom selected from O / N / S; C _1-10 alkyl, cycloalkyl or cycloalkyl alkyl groups such as methyl, ethyl, propyl, isopropyl, t-butyl and the like, or cyclopropylmethyl; Halo substituted C _1-10 alkyl, for example, -CF ₂ CF ₂ H or -CF ₃ ; Means a group such as an optionally substituted aryl such as phenyl or optionally substituted arylalkyl such as benzyl or phenethyl, wherein the aryl moiety may also be substituted with halogen; Hydroxy; Hydroxy substituted alkyl; C _1-10 alkoxy; S (O) m alkyl; Amino, mono- and di-substituted amino (as for example in NR ₇ R ₁₇ ); Alkyl or CF < ₃ >.

Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include those salts which are well known to those skilled in the art and include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, Salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts of the compounds of general formula I may also be formed using pharmaceutically acceptable cations, for example when the substituent group comprises a carboxy moiety. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali metals, alkaline earth metals, ammonium and quaternary ammonium cations.

The terms used herein have the following meanings:

&Quot; Halo " or " halogen " includes halogen: chloro, fluoro, bromo and iodo.

Unless otherwise limited the term " C _1-10 alkyl " or " alkyl " -chain, both refer to straight and branched radicals of 1 to 10 carbon atoms and include methyl, ethyl, n- n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like.

The term " cycloalkyl " as used herein preferably means a cyclic radical of 3 to 8 carbons and includes, but is not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like.

The term " cycloalkenyl " as used herein means a cyclic radical, preferably of 5 to 8 carbon atoms, having at least one double bond, including cyclopentenyl, cyclohexenyl, and the like, But is not limited thereto.

As used herein, the term " alkenyl " means a straight or branched chain radical of 2 to 10 carbon atoms, and unless otherwise limited in chain length, ethenyl, 1-propenyl, 2- 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.

&Quot; aryl " -phenyl and naphthyl.

- "heteroaryl" (by itself or in any combination, such as "heteroaryloxy" or "heteroarylalkyl") - an aromatic ring system of 5-10 members wherein one or more rings N, O or S, and includes, for example, at least one hetero atom selected from the group consisting of pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, But are not limited to, sol, thiadiazole, triazole, imidazole or benzimidazole.

&Quot; Heterocyclic " (by itself or in any combination, e. G., &Quot; heterocyclylalkyl ") - a ring system of 4-10 members saturated or partially unsaturated, wherein one or more rings Includes one or more heteroatoms selected from the group consisting of N, O or S and includes, for example, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran or imidazolidine, It does not.

&Quot; Aralkyl " or " heteroarylalkyl " or " heterocyclic alkyl ", as used herein, unless otherwise indicated, are as defined hereinabove bonded to an aryl, heteroaryl or heterocyclic moiety as defined herein, Means the same C _1-4 alkyl.

The term " sulfinyl " - the corresponding sulphide oxide S (O), the term "thio" denotes sulfide and the term "sulfonyl" denotes the fully oxidized S (O) ₂ moiety.

Ar0 is phenyl, naphthyl, or an arylalkyl derivative as defined above, including but not limited to benzyl and phenethyl.

&Quot; Alkanoyl " - C (O) C _1-10 alkyl, wherein alkyl is as defined above.

The "core" 4-pyrimidinyl moiety for R ₁ or R ₂ for the purposes herein is illustrated by the following formula.

The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are included within the scope of the present invention.

Exemplary compounds of formula I include,

4- (4-fluorophenyl) -5- (2-phenoxypyrimidin-4-yl) imidazole

4- (4-fluorophenyl) -5- (2-phenoxy-4-pyridinyl) imidazole

4- (4-fluorophenyl) -5- [2- (4-methoxyphenoxy) -4-pyridinyl] imidazole

4- (4-fluorophenyl) -5- [2- (4-fluorophenoxy) -4-pyridinyl] imidazole

4- (4-fluorophenyl) -5- [2- (4-methoxyphenoxy) pyrimidin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2- (4-fluorophenoxy) pyrimidin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2- (4-aminocarbonylphenoxy) pyrimidin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2- (4-ethylphenoxy) pyrimidin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2- (4-benzyloxyphenoxy) pyrimidin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2- (4-cyanophenoxy) pyrimidin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2- (4-hydroxyphenoxy) pyrimidin-4-yl] -imidazole

4- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5- [2- (phenoxy) pyrimidin-

4- (4-fluorophenyl) -5- [2- (2,6-dimethylphenoxy) pyridin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2- (4-methylphenoxy) pyridin-4-yl]

4- (4-fluorophenyl) -5- [2- (4-chlorophenoxy) pyridin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2- (phenoxy) pyrimidin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2- (3-methoxyphenoxy) pyrimidin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2- (4-phenylphenoxy) pyrimidin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2- (4-phenoxyphenoxy) pyrimidin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2- (3-hydroxyphenoxy) pyrimidin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2- (4-fluorophenoxy) pyrimidin-4- yl] imidazole

4- (4-fluorophenyl) -5- [2- (2-hydroxyphenoxy) pyrimidin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2 - ((3,4-methylenedioxy) phenoxy) pyrimidin-

4- (4-fluorophenyl) -5- [2- (3-fluorophenoxy) pyrimidin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2- (2-fluorophenoxy) pyrimidin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2- (2-methoxyphenoxy) pyrimidin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2- (3-trifluoromethylphenoxy) pyrimidin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2- (3,4-difluorophenoxy) pyrimidin-4-yl] -imidazole

4- (4-fluorophenyl) -5- [2- (4-methylsulfonylphenoxy) pyrimidin-4-yl] -imidazole

4- (4-fluorophenyl) -5- (2-thiophenoxypyrimidin-4-yl) -imidazole

4- (4-fluorophenyl) -5- [2- (1-methyltetrazol-5-ylthio) pyridin-

.

Compounds of general formula I can be obtained by applying synthetic procedures, some of which are illustrated in the following Schemes I to XI. To conform to the reactions outlined herein, the synthetic methods provided in these schemes are applied to the preparation of compounds of the general formula I having very different R ₁ , R ₂ and R ₄ groups to be reacted with any suitably protected substituents . In this case, then, in the case of the above case, subsequent deprotection gives compounds of the generally disclosed properties. The reaction scheme represents a compound of formula I wherein Y is oxygen, and one of ordinary skill in the art can readily prepare the compound of formula I wherein Y is sulfur using a similar reaction method in the examples herein.

Once imidazole nuclei are formed, other compounds of general formula I can be prepared by applying standard techniques for functional group transformation known in the art. For example, from HNR ₁₃ R ₁₄ and -CO ₂ CH _{3 in} CH ₃ OH to -C (O) NR ₁₃ R ₁₄ by heating with or without a catalytic metal cyanide, for example NaCN; Pyridine of ClC (O) R ₃ using a -OC (O) R ₃ from -OH; From -NHR ₁₀ to -NR ₁₀ -C (S) NR ₁₃ R ₁₄ using alkyl isothiocyanate or thiocyanic acid; From -NHR ₆ to -NR ₆ C (O) OR ₆ using alkyl chloroformate; From an -NHR ₁₀ to an -NR ₁₀ C (O) NR ₁₃ R ₁₄ by treating with an isocyanate such as NH = C = O or R ₁₀ N = C = O; Pyridine of _{Cl-C (O) -NR 10} -C (O) from -NHR ₁₀ by treatment with R ₃ to R _8; From -C (NR ₁₃ R ₁₄ ) SR ₃ to -C (═NR ₁₀ ) NR ₁₃ R ₁₄ using H ₃ NR ₃ ⁺ OAc ^- by heating in alcohol; From -C (S) NR ₁₃ R ₁₄ to -C (NR ₁₃ R ₁₄ ) SR ₃ using R ₆ -I in an inert solvent such as acetone; C (S) NR ₁₃ R ₁₄ (wherein R ₁₃ and R ₁₄ are not hydrogen) from C (S) NH ₂ using HNR ₁₃ R ₁₄ ; By heating in anhydrous alcohol with a _{NH 2 CN -C (= NR 13} R 14) processes from -SR _3, in EtOH Alternatively of BrCN and NaOEt -C (= NH) -C from -NR ₁₃ R ₁₄ ( = NCN) -NR < ₁₃ > R < _{14 &} gt ;; (R ₈ S) ₂ C = NCN to yield -NHR ₁₀ to -NR ₁₀ -C (= NCN) SR ₈ ; By heating in pyridine by treatment with ClSO ₂ R ₃ by -NR ₁₀ SO ₂ R ₃ from -NHR _10; Wesson as by treatment with a reagent [2,4-bis (4-methoxyphenyl) -1,3,2,4- dithio adipic force petan-2,4-disulfide] from -NR ₁₀ C (O) R ₈ -NR < ₁₀ > C (S) R < ₃ >; Using triflic anhydride and a base with -NR ₁₀ SO ₂ CF ₃ from -NHR _{6 (here, R 3, R 6, R} 10, R 13 and R ₁₄ are as defined in formula I herein, ).

The precursors of the R _1, R ₂ and R ₄ groups may be other R _1, R ₂ and R ₄ groups that can be converted by applying standard techniques for functional group conversion. For example, a compound of general formula I wherein R < ₂ > is halo-substituted C _1-10 alkyl can be converted to the corresponding C _1-10 alkyl N ₃ derivative by reaction with a suitable azide salt, C _1-10 alkyl may be reduced to NH ₂ compound, this _{re-R 18 S (O) 2 X} ( here, X is halo (e.g., chloro) a) to give the corresponding C _1-10 to which Alkyl NHS (O) ₂ R < ₁₈ > compound.

Alternatively, a compound of formula I wherein R ₂ is halo-substituted C _1-10 alkyl can be reacted with an amine R ₁₃ R ₁₄ NH to give the corresponding C _1-10 alkyl NR ₁₃ R ₁₄ compound, or R ₁₈ < / RTI > SH to give the corresponding < RTI ID = 0.0 > _C10 < / RTI > alkyl SR ₁₈ compound.

Referring to Scheme I, the compounds of general formula I are suitably prepared by reacting a compound of general formula II with a compound of general formula III, wherein p is 0 or 2, R ₁ , R ₂ and R ₄ are generic as stated above for the formula I, or, R _1, R ₂ and is a precursor of R ₄ group, Ar is optionally a substituted phenyl group), if necessary R _1, R ₂ and R ₄ precursor of R _1, R ₂ of And R < ₄ > groups. In R ₂ NH ₂ , which reacts with R ₁ CHO to form an imine of the general formula III, the R ₂ moiety requires a suitable protecting group when it comprises a reactive functional group, for example a primary or secondary amine, an alcohol or a thiol compound . Suitable protecting groups can be found in Protecting Groups in Organic Synthesis, Greene TW, Wiley-Interscience, New York, 1981, incorporated herein by reference. For example, when R ₂ comprises a heterocyclic ring such as a piperidine ring as a substituent, the nitrogen is protected with a group such as t-Boc, CO ₂ R ₁₈ or a substituted arylalkyl moiety.

Suitably the reaction is carried out in the presence of a suitable base such as K ₂ CO ₃ , t-buNH ₂ , 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), or a guanidine base, Such as, for example, methylene chloride, DMF, tetrahydrofuran, toluene, acetonitrile or dimethoxyethane in the presence of, for example, 1,5,7-triaza-bicyclo [4.4.0] In an inert solvent at ambient temperature, or by cooling (e.g., -50 ° C to 10 ° C). The intermediates of general formula II were found to be very stable and long-term storage. Preferably, p is 2. PCT is defined herein as the use of a phase transfer catalyst.

The compound of formula II has the following structure.

Wherein p is 0 or 2, R ₄ is as defined in formula I, and Ar is aryl optionally substituted as defined herein. Suitably, Ar is phenyl optionally substituted by C _1-4 alkyl, C _1-4 alkoxy or halo. Preferably, Ar is 4-methylphenyl, such as a phenyl or tosyl derivative.

When p = 2, the reaction of a compound of general formula II with a compound of general formula III (Scheme I) provides a compound of general formula I at a constant higher yield when p = 0. In addition, the reaction of the compound of formula II (p = 2) is more environmentally economically preferred. The preferred solvent used when p = 0 is methylene chloride, which is environmentally less preferred for large-scale processing, as compared to using the commercially preferred synthesis (p = 2) as further described herein, TBD is also expensive and produces some by-products and impurities.

As noted above, Scheme I utilizes a reaction in which a substituted aniline of arylthiomethylisocyanide (when p = 0) is 1,3-dipolar cycloaddition to the imine. More specifically, the reaction requires strong bases such as amine bases for use in the deprotonation step. t-Butoxide, Li + or Na + or K + hexamethyldisilazide can also be used, but commercially available TBD is preferred. Although methylene chloride is the preferred solvent, other halogenated solvents such as chloroform or carbon tetrachloride; Ethers such as THF, DME, DMF, diethyl ether, t-butyl methyl ether; In addition, acetonitrile, toluene or a mixture thereof may be used. For reactions involving R ₁ groups that are pyrimidines, the reaction is carried out at a temperature of from about -20 캜 to about 40 캜, preferably from about 0 캜 to about 23 캜, more preferably from about 0 캜 to about 10 캜, RTI ID = 0.0 > 4 C. < / RTI > It may be appreciated that for compounds wherein R < _{1 >} is pyridine, it may be necessary to vary both the temperature and the reaction conditions of the solvent, such as, for example, lowering the temperature to about -50 DEG C or changing the solvent to THF.

In a further process, the compound of general formula I is represented by the general formula IX

Wherein T ₁ is hydrogen and T ₄ is R ₄ or alternatively T ₁ is R ₁ and T ₄ is H wherein R _1, R ₂ and R ₄ are as defined above, ≪ / RTI >

(i) T ₁ is the case of hydrogen, to the coupling reaction with a suitable derivative of the heteroaryl ring R ₁ H under ring coupling conditions, the imidazole nucleus of the heteroaryl ring R ₁ position 5;

(ii) when T < ₄ > is hydrogen, the aryl ring R < ₄ > is bonded to a suitable derivative of the aryl ring R < _{4 &}

And the like.

The aryl / heteroaryl bonding reaction is well known to those skilled in the art. Generally, organometallic synthetic equivalents of one component anion are combined with a reactive derivative of the second component in the presence of a suitable catalyst. Anion equivalents can be formed from both an imidazole of the general formula IX (in which case the aryl / heteroaryl compound provides a reactive derivative) or an aryl / heteroaryl compound (in which case the imidazole provides a reactive derivative) . Thus, the compounds of formula IX or suitable derivatives of the aryl / heteroaryl ring include organometallic derivatives such as organomagnesium, organozinc, organotin and boronic acid derivatives, suitable reactive derivatives include bromo, iodo , Fluorosulfonate, and trifluoromethanesulfonate derivatives. Suitable procedures are described in WO 91/19497, incorporated herein by reference.

Suitable organomagnesium and organozinc derivatives of compounds of general formula IX can be prepared by reacting a ring-coupling catalyst, such as palladium (0), according to the procedure of Kumada et al., Tetrahedron Letters, 22, 5319 (1981) Or with a halogen, fluorosulfonate or triflate derivative of a heteroaryl or aryl ring in the presence of a palladium (II) catalyst. Such suitable catalysts include tetrakis- (triphenylphosphine) palladium and PdCl ₂ [1,4-bis- (diphenylphosphino) -butane] palladium in the presence of lithium chloride and a base, . In addition, nickel (II) catalysts such as Ni (II) Cl ₂ (1,2-biphenylphosphino) ethane are also described in Pridgen et al., J. Org. Chem. 1982, 47, 4319]. ≪ / RTI > Suitable reaction solvents include hexamethylphosphoramide. When the heteroaryl ring is 4-pyridyl, suitable derivatives include 4-bromo- and 4-iodo-pyridine, and fluorosulfonates of 4-hydroxypyridine and triflate esters. Similarly, when the aryl ring is phenyl, suitable derivatives include bromo, fluorosulfonates, triflates and preferably iodo-derivatives. Suitable organomagnesium and organozinc derivatives can be obtained by treating the compound of formula IX or its bromo derivative with an alkyl lithium compound, respectively, by deprotonation or by transmetalation to obtain the corresponding lithium reagent. This lithium intermediate can then be treated with an excess of magnesium halide or zinc halide to give the corresponding organometallic reagent.

Trialkyl tin derivatives of compounds of formula IX are described in Stille, J. Amer. Chem. (0) catalyst, such as tetrakis- (triphenylphosphine) -palladium, by the methods described in U.S. Patent Nos. 4,719,218 and 5,002,942, In the presence of a coupling catalyst, preferably in an inert solvent comprising 10% hexamethylphosphoramide, such as a bromide, fluorosulfonate, triflate or preferably triflate of an aryl or heteroaryl ring compound in tetrahydrofuran Can be treated by treatment with an iodide derivative or by treatment with a palladium (II) catalyst in the presence of lithium chloride optionally in the presence of a base such as triethylamine in an inert solvent such as dimethylformamide. Trialkyltin derivatives are conveniently prepared by metallating a corresponding compound of formula IX with a lithiating agent such as s-butyl-lithium or n-butyl lithium in an ether solvent, such as tetrahydrofuran, Treating the bromo derivative of the compound of formula IX with an alkyllithium and then treating with a trialkyltin halide in each case. Alternatively, the bromo-derivative of the compound of formula IX may be treated with a suitable heteroaryl or aryltrialkyltin compound in the presence of a catalyst such as tetrakis- (triphenyl-phosphine) -palladium under similar conditions as described above .

Boronic acid derivatives may also be used. Thus, suitable derivatives of compounds of formula IX, such as bromo, iodo, triflate, and fluorosulfonate derivatives, can be prepared by reacting a compound of formula IX with a suitable base such as tetra Can be reacted with a heteroaryl- or aryl-boronic acid in the presence of a palladium catalyst such as kiss- (triphenylphosphine) -palladium or PdCl ₂ [1,4-bis- (diphenylphosphino) -butane] [Fisher and Haviniga, Rec. Trav. Chim. Pays Bas, 84, 439, 1965], Snieckus, V., Tetrahedron Lett., 29, 2135 , 1988, and Terashimia, M., Chem. Pharm. Bull., 11, 4755, 1985). Solvents such as DMF can also be used in the presence of a Pd (II) catalyst at non-aqueous conditions, for example at a temperature of about 100 ° C (Thompson, WJ et al., J. Org. Chem , 49, 5237, 1984). Suitable boronic acid derivatives can be prepared by treating the magnesium or lithium derivative with a trialkyl borate ester, such as triethyl, tri-iso-propyl or tributyl borate, according to standard procedures.

In the coupling reaction, it will be readily appreciated that appropriate attention should be paid to the aspects of the functional groups present in the compounds of formula IX. Thus, in general, the amino and sulfur substituents should not be oxidized or protected.

The compound of formula IX is imidazole and can be obtained by any of the procedures described above for preparing compounds of formula I. [ In particular, α- halo-ketone or other suitably activated ketones R ₄ COCH ₂ Hal (T ₁ is hydrogen in the compound of formula IX) or R ₁ COCH ₂ Hal (T ₄ the compound of formula IX hydrogen to about) a halogenated hydrocarbon solvent, for example, if at the appropriate elevated temperature in an inert solvent such as chloroform, if necessary, of the general formula R ₂ NH-C = NH (here, in the presence of a suitable condensing agent such as a base, R ₂ is Lt; RTI ID = 0.0 > I) < / RTI > or a salt thereof. The preparation of suitable? -Halo-ketones is described in WO 91/19497. Suitable reactive esters include esters of strong organic acids such as lower alkanesulfonic acids or arylsulfonic acids, e.g., methane or p-toluenesulfonic acid. Amidine is preferably used as a salt, suitably as a hydrochloride salt, and then the reactive ester is present in an inert organic solvent such as chloroform and the salt is present in an aqueous phase which is slowly added with vigorously stirring 2 moles of an aqueous base solution Lt; / RTI > can be converted to free amidines in situ by using a two-phase system. Suitable amidines may be obtained by standard methods (see, for example, Garigipati R, Tetrahedron Letters, 190, 31, 1989).

Compounds of general formula I are also disclosed in U. S. Patents 4,803, 279; Reacting a compound of formula IX wherein T < ₁ > is hydrogen with an N-acylheteroaryl salt according to the method described in U.S. Pat. Nos. 4,719,218 and 5,002,942 to prepare a compound wherein the heteroaryl ring is attached to the imidazole nucleus , An intermediate present as its 1,4-dihydro derivative, and then treating the intermediate with oxidative-deacylation conditions (scheme II). The heteroaryl salts, such as pyridinium salts, can be prepared by reacting a substituted carbonyl halide (e.g., an acyl halide, an aroyl halide, an arylalkyl haloformate ester or preferably an alkyl haloformate ester, , Acetyl bromide, benzoyl chloride, benzyl chloroformate or preferably ethyl chloroformate) in an inert solvent, such as methylene chloride, in a heteroaryl compound R < ₁ > H or with a heteroaryl compound, , Or more preferably in situ. Suitable deacylation and oxidation conditions are described in U.S. Patent Nos. 4,803,279, 4,719,218 and 5,002,942, the disclosures of which are herein incorporated by reference. Suitable oxidation systems include, but are not limited to, in an inert solvent or solvent mixture such as decalin, decalin and diglyme, sulfur in p-cymene, xylene or mesitylene under reflux conditions, or potassium in t- t-butoxide.

In a further process illustrated in Scheme III below, compounds of general formula I can be prepared by treating the compound of general formula X thermally or with the aid of a cyclizing agent such as phosphorus oxychloride or phosphorus pentachloride (for example, See Engel and Steglich, Liebigs Ann Chem, 1978, 1916, and Strzybny et al., J. Org. Chem. 1963, 28, 3381). Compounds of formula X can be prepared, for example, by acylating the corresponding? -Keto-amine with an activated formate derivative such as the corresponding anhydride under standard acylation conditions and then forming an imine using R ₂ NH ₂ . Amino ketones can be derived from oxetamines and reduction from moieties and the requisite ketones are again prepared by decarboxylating the beta-keto esters obtained from the condensation reaction of the aryl (heteroaryl) acetic acid ester with the R ₁ COX component .

In Scheme IV below, two (2) different routes are illustrated using ketones (Formula XI) to prepare compounds of Formula I. [ Heterocyclic ketones (general formula XI) can be prepared by reacting an anion of an alkyl heterocycle such as 4-methyl-quinoline (prepared by treating the alkylheterocycle with alkyl lithium such as n-butyllithium) Amides, esters or any other suitably activated derivatives of the same oxidation state. Alternatively, the anion can be condensed with benzaldehyde to give an alcohol and then oxidized to the ketone (Formula XI).

In a further process, the N-substituted compound of formula I is a compound of formula XII

R ₁ CH ₂ NR ₂ COH

(Wherein R < ₁ > and R < ₂ > are as defined above)

(a) < RTI ID = 0.0 >

R ₄ CN

(Wherein R < ₄ > is as defined above); or

(b) an excess of a compound of the general formula XIV

R ₄ COHal

Is treated with an acyl halide, such as an acyl chloride, or a corresponding anhydride, of the formula: wherein R ₄ is as defined above and Hal is halogen, to obtain a bis-acylated intermediate, which is then reacted with ammonium acetate By treating with the same ammonia source.

A variation of the above method is illustrated in Scheme V above. Treatment of the primary amine (R ₂ NH ₂ ) with a halomethyl heterocycle of the general formula R ₁ CH ₂ X gives the secondary amine which is then converted to the amide by standard techniques. Alternatively, the amide may be prepared as illustrated in scheme V by alkylation of the formamide with R ₂ CH ₂ X. The deprotonation of the amide with an amide strong base such as lithium di-iso-propylamide or sodium bis- (trimethylsilyl) amide followed by the addition of excess aroyl chloride gives the bis-acylated compound Then, cyclization by heating in acetic acid containing ammonium acetate gives the imidazole compound of general formula I. Alternatively, the anion of the amide can be reacted with the substituted aryl nitrile to produce the imidazole of formula I directly.

The following description and schemes are additional examples of methods as described above in Scheme I. The various pyrimidine aldehyde derivatives 6, 7 and 8 shown in Scheme VI below can be prepared as described in Bredereck et al., Chem. Ber. 1964, 97, 3407]. The pyrimidine aldehyde is then used as an intermediate in synthetic methods as further described herein.

The reaction of imines with tosylmethylisononitrile is described in van Leusen et al., J. Org. Chem. 1977, 42, 1153]. Conditions such as tertiary butylamine (tBuNH ₂ ) in dimethoxyethane (DME), K ₂ CO _{3 in} MeOH, and NaH in DME have been reported. A re-examination of each of these conditions revealed that a low yield was obtained. A second route was also made, comprising preparing t-butylimine by amine exchange followed by reaction with isocyanide to produce 1-tBu imidazole. This route will probably be carried out using any primary amine as the base. Although not preferred, secondary amines can be used, but they can also slowly decompose isonitrile. The reaction will probably require about 3 equivalents of amine to complete, yielding an isolation yield of about 50%. Protected secondary amines (diisopropylamine) are available, but are very slow and generally not very effective. Using tertiary and aromatic amines such as pyridine and triethylamine did not cause a reaction under certain test conditions and the more basic types such as DBU and 4-dimethylaminopyridine (DMAP) gave slow but slight yields , And thus may be suitable for use herein.

As exemplified in Scheme VII and VIII below, the pyrimidine aldehyde of Scheme VI may be condensed with a primary amine to produce an imine which may be suitably isolated or reacted with various suitable bases in situ Can be reacted with the desired isonitrile in the presence of a solvent to give 5- (4-pyrimidinyl) -imidazole, wherein R ₂ and R ₄ are as defined for compounds of general formula I, .

One preferred method for preparing compounds of general formula I is shown in Scheme VII below. Immigration is often difficult to handle and is produced and isolated in separate stages. Also often black is carried over to the final product. The yields for preparing imines vary and environmentally less acceptable solvents such as CH ₂ Cl ₂ are often used in their preparation.

In the reaction (p = 2), a suitable base is required to proceed the reaction. The reaction requires a base that is strong enough to deprotonate isonitrile. Suitable bases include amines, carbonates, hydrides or alkyl or aryl lithium reagents; Or mixtures thereof. The base may be selected from the group consisting of potassium carbonate, sodium carbonate, primary and secondary amines such as t-butylamine, diisopropylamine, morpholine, piperidine, pyrrolidine and other non-nucleophilic bases such as DBU, But are not limited to, DMAP and 1,4-diazabicyclo [2.2.2] octane (DABCO).

Suitable solvents for use herein include N, N-dimethyl-formamide (DMF), MeCN, halogenated solvents such as methylene chloride or chloroform, tetrahydrofuran (THF), dimethoxysulfoxide (DMSO) , Alcohols such as methanol or ethanol, benzene, toluene, DME or EtOAc. Preferably, the solvent is DMF, DME, THF, or MeCN, more preferably DMF. Isolation of the product can generally be carried out by adding water and filtering the product as a pure compound.

It may not be convenient for large-scale operation, but it may be necessary to add NaH instead of t-butylamine to isonitrile (in THF) while lowering the temperature to below 25 ° C. BuLi has also been reported to be an effective base for the deprotonation of tosylbenzylisonitrile at -50 ° C (DiSanto et al., Synth. Commun. 1995, 25, 795].

Various temperature conditions can be used depending on the desired base. For example, in the case of t-BuNH ₂ / DME, K ₂ CO ₃ / MeOH, K ₂ CO _{3 in} DMF, at a temperature above about 40 ° C., the yield may drop to about 20% Little is expected. Consequently, temperature ranges below 0 ° C and above 80 ° C are also considered to be within the scope of the present invention. Preferably, the temperature range is from about 0 ° C to about 25 ° C. For purposes of the present invention, it is recognized that the room temperature described at 25 占 폚 may vary from 20 占 폚 to 30 占 폚.

As shown in Scheme VIII below, the imine is preferably formed in situ in a solvent. This preferred synthesis method is a process that takes place in a 1-reaction vessel synthesis method. Suitably, when a primary amine is used as a salt such as a hydrochloride salt in the following examples, the reaction may further comprise a base such as potassium carbonate prior to the addition of the isonitrile. Alternatively, the piperidine nitrogen may be required to protect (PG), as shown below, suitably PG is BOC or C (O) ₂ R, wherein R is preferably Aryl, arylalkyl moieties.

Reaction conditions such as solvent, base, temperature, and the like are similar to those illustrated and discussed above for the isolated imines as shown in Scheme VII. Those skilled in the art will readily recognize that, under some circumstances, dehydrating conditions may be required in the formation of imines in situ, or that acid catalysts may be required.

Scheme IX below is another method of preparing other compounds of formula I. In particular cases, the alkylthio moiety is oxidized to the methylsulfinyl or sulfonyl moiety and is reacted with the appropriate YR _a moiety.

Another embodiment of the present invention is a novel hydrolysis of a 2-thiomethylpyrimidine acetal to a 2-thiomethyl or alkoxypyrimidine aldehyde, as shown in Scheme X below. Hydrolysis of an acetal to an aldehyde using various known reaction conditions such as formic acid yields less than 13% of the yield of the aldehyde unsatisfactory. The preferred synthesis involves the use of AcOH (fresh) as solvent, and concentrated H ₂ SO ₄ , preferably a catalytic amount of sulfuric acid, under heating conditions. Since high temperatures darken the reaction mixture, the heating conditions include temperatures of about 60 to 85 占 폚, preferably about 70 to about 80 占 폚. After the reaction is complete, the mixture is cooled to about room temperature and the acetic acid is removed. The alternative procedure involves heating the acetal in 3N HCl at 40 < 0 > C for about 18 hours, cooling, and extracting the bicarbonate neutral solution into EtOAc.

2- (R _a Y) -pyrimidin-4-ylimidazole compounds of the general formula I as well as similar pyridine containing compounds can be prepared by three methods: 1) reaction of 2- (R _a Y) alkoxypyrimidineimine with isonitrile 2) the oxidation of a 2-alkylthiopyrimidine derivative to the corresponding sulfoxide, followed by the use of a metal salt of, for example, HYR _a , or in the presence of a non-nucleophilic amine or alkyllithium base, Substitution with HYR _a 3) reaction of 2-halopyrimidine or pyridine imine with isonitrile followed by substitution with HYR _a under the base conditions described in the second method (Adams et al., USSN 08 / 659,102 1996 6 Filed March 3, see Scheme XI-the entirety of which is incorporated herein by reference).

These reaction schemes may be represented, for example, by an optionally substituted cyclohexyl moiety for the resulting R ₂ position, or by ₄ -fluorophenyl for R ₄ , while any suitable R ₂ moiety or R ₄ may be prepared on a primary amine If you can, you can go this way. Similarly, any suitable R < ₄ > may be added via isonitrile.

In Scheme I, the compound of formula II can be prepared by the method of Van Leusen et al. For example, a compound of formula II can be prepared by dehydrating a compound of formula IV (Scheme I, wherein Ar, R ₄ and p are as defined herein).

Suitable dehydrating agents include acid chlorides, oxalyl chloride, thionyl chloride, phosgene or tosyl chloride in the presence of a suitable base such as triethylamine or diisopropylethylamine or the like, or the like, such as pyridine. Suitable solvents are dimethoxy ether, tetrahydrofuran, or halogenated solvents, preferably THF. The reaction is highly efficient when the reaction temperature is maintained between -10 ° C and 0 ° C. The reaction occurs incompletely at low temperature, and the solution becomes dark at high temperature and the yield of the product lowers.

The compound of formula IV (Scheme I) can be prepared by reacting a compound of formula V (Scheme I), optionally in the presence of an acid catalyst, conveniently under reflux, at ambient or elevated temperature, for example 30-150 & , R ₄ CHO, wherein R ₄ is as defined herein, with ArS (O) _p H and formamide, without removal or removal of water. Alternatively, trimethylsilyl chloride can be used in place of the acid catalyst. Examples of the acid catalyst include camphor-10-sulfonic acid, formic acid, p-toluenesulfonic acid, hydrogen chloride or sulfuric acid.

The optimal method for the preparation of isonitrile of formula II is illustrated in Scheme XI below.

Conversion of the substituted aldehyde to tosyl benzylformamide can be accomplished by heating aldehyde 1 (Scheme XI) with p-toluenesulfonic acid, formic acid, or camphorsulfonic acid, with formamide and p-toluene- Under the reaction conditions for a period of time. Preferably, no solvent is used. If a solvent such as DMF, DMSO, toluene, acetonitrile, or excess formamide is used, the yield is poor (less than 30%). Temperatures below 60 ° C are generally poor for making the desired product, temperatures above 60 ° C may produce degraded products, or benzylbis-formamide 2 (Scheme XI).

Another embodiment of the present invention is the synthesis of a tosyl benzylformamide compound achieved by reacting bisformamide intermediate 2 (Scheme XI) with p-toluenesulfinic acid. In this preferred route, the preparation of the bisformamide from the aldehyde is accomplished by heating the aldehyde with the acid catalyst in a suitable solvent with formamide. Suitable solvents are toluene, acetonitrile, DMF and DMSO or mixtures thereof. Acid catalysts are well known in the art and include, but are not limited to, hydrogen chloride, p-toluenesulfonic acid, camphorsulfonic acid, and other anhydrous acids. The reaction may be carried out at a temperature in the range of about 25 to 110 DEG C, preferably about 50 DEG C, suitably for about 4 to about 5 hours, and longer reaction times may also be acceptable. Product degradation and water retention can be observed at extended reaction times at high temperatures (greater than 70 ° C). In general, complete conversion of the product requires the removal of water from the reaction mixture.

Preferred conditions for converting the bisformamide derivative to tosyl benzylformamide are achieved by heating bisformamide with an acid catalyst and p-toluenesulfinic acid in an appropriate solvent. The solvents used in this reaction include, but are not limited to, toluene and acetonitrile or mixtures thereof. Additional mixtures of these solvents with DMF or DMSO may also be used but yields may be reduced. The temperature ranges from about 30 to about 100 < 0 > C. Temperatures below 0 < 0 > C and temperatures above 60 < 0 > C are undesirable because of reduced yield and rate. Preferably, the range is from about 40 to 60 DEG C, most preferably about 50 DEG C. The optimum time may be longer, but is about 4 to 5 hours. Preferably, the acids used include, but are not limited to, toluenesulfonic acid, camphorsulfonic acid, and hydrogen chloride and other anhydrous acids. Most preferably, the bisformamide is heated with p-toluenesulfinic acid and hydrogen chloride in a 1: 1 ratio of toluene: acetonitrile.

Another embodiment of the present invention is a preferred synthetic route for the synthesis of tosyl benzyl formamides achieved using a one-step process. This process first converts the aldehyde to the bisformamide derivative, and subsequently reacts the bisformamide with toluenesulphonic acid. This process combines the optimized conditions into a single efficient process. A high yield of more than 90% of aryl benzylformamide can be obtained in this way.

Preferred reaction conditions employ a catalyst such as trimethylsilyl chloride in a preferred solvent, preferably 1: 1 toluene: acetonitrile. Reagents such as TMSCl which react with the produced water and simultaneously produce hydrogen chloride to promote the reaction are preferred. It is also preferred to use hydrogen chloride and p-toluenesulfonic acid. Thus, three suitable reaction conditions for use herein include 1) the use of a dehydrating agent such as TMSCl, which also provides hydrogen chloride, 2) an appropriate source of suitable dehydrating agent and acid source, such as camphorsulfonic acid, hydrogen chloride or toluene sulfonic acid , And 3) alternative dewatering conditions, such as azeotropic removal of water and use of an acid catalyst and p-toluenesulfinic acid.

Compounds of formula II wherein p is 2 can also be prepared by reacting a compound of formula VI (Scheme I), R ₄ CH ₂ NC with a compound of formula VII (Scheme I), ArSO ₂ L ₁ , R ₄ and Ar are as defined herein and L ₁ is a leaving group such as halo, for example fluoro. Suitable strong bases include, but are not limited to, alkyllithium, such as butyllithium or lithium diisopropylamide (van Leusen et al., Tetrahedron Letters, No. 23, 2367-68 (1972)).

The compound of formula VI (Scheme I) can be prepared by reacting a compound of formula VIII (Scheme I), R ₄ CH ₂ NH ₂ with an alkyl formate (for example, ethyl formate) to give the intermediate amide, In the presence of a dehydrating agent such as oxalyl chloride, phosphorus acid chloride or tosyl chloride in the presence of a suitable base such as triethylamine to give the isonitrile.

Alternatively, the compound of formula VIII (Scheme I) can be converted to the compound of formula VI (Scheme I) by reaction with chloroform and sodium hydroxide in aqueous dichloromethane under a phase transfer catalyst.

The compound of formula III (scheme I) can be prepared by reacting a compound of formula R ₁ CHO with a primary amine R ₂ NH ₂ .

The amino compounds of the general formula VIII (scheme I) are known or can be prepared from the corresponding alcohols, oximes or amides using standard functional group interconversions.

Suitable protecting groups with hydroxyl groups and imidazole nitrogen are well known in the art and are described in many references (e.g. Protecting Groups in Organic Synthesis, Greene TW, Wiley-Interscience, New York, 1981). Suitable examples of hydroxyl protecting groups include silyl ethers such as t-butyldimethyl or t-butyldiphenyl, and alkyl ethers such as methyl linked by an alkyl chain (CR ₁₀ R ₂₀ ) _n of a variable bond. Suitable examples of imidazole nitrogen protecting groups include tetrahydropyranyl.

The pharmaceutically acceptable acid addition salts of the compounds of the general formula I can be obtained by known methods, for example by treatment with a suitable amount of acid in the presence of a suitable solvent.

Treatment method

The compounds of general formula I, or pharmaceutically acceptable salts thereof, are exacerbated by excessive or unregulated cytokine production by cells of the mammal (such as, but not limited to, mononuclear cells and / or macrophages) Or for the manufacture of a medicament for the prevention or treatment of the disease state of a human or other mammalian subject.

Compounds of general formula I are capable of inhibiting pro-inflammatory cytokines such as IL-1, IL-6, IL-8 and TNF and are therefore useful for therapy. IL-1, IL-6, IL-8 and TNF are important, mediators of critical inflammatory conditions of various disease states and conditions, as well as other leukocyte-derived cytokines, as well as various effects on cells and tissues and on such cytokines. This inhibition of proinflammatory cytokines is useful in modulating, reducing and alleviating a number of such disease states.

Accordingly, the present invention provides a method of treating a cytokine-mediated disease comprising administering an effective amount of a compound of general formula I, or a pharmaceutically acceptable salt thereof, to a cytokine-interfering effective amount.

Compounds of the general formula I can inhibit proinflammatory proteins such as COX-2, and can also inhibit various types of prostaglandin endoperoxide synthase-2 (PGHS-2), such as prostaglandin endoperoxide synthase-2 It is called by other names and is therefore useful for treatment. This proinflammatory lipid mediator of the cyclooxygenase (CO) pathway is produced by the inducible COX-2 enzyme. Thus, modulation of COX-2 due to these products from arachidonic acid, for example, prostaglandins, is important and has a variety of effects on cells and tissues and is a mediator of critical inflammation of various disease states and conditions. The expression of COX-1 is not affected by the compounds of the general formula I. Such selective inhibition of COX-2 can alleviate or eliminate the ulcer-inducing tendency associated with the inhibition of COX-1, thereby inhibiting progesterone, which is essential for the cytoprotective effect. Thus, inhibition of such proinflammatory mediators is useful for modulating, reducing, or alleviating a number of such disease states. Most prominent these proinflammatory mediators, especially prostaglandins, are associated with pain, such as increased or decreased pain receptors, or edema. This aspect of pain control thus includes the treatment of neuromuscular pain, headache, cancer pain and arthritis pain. The compounds of general formula I, or a pharmaceutically acceptable salt thereof, are useful for the prophylaxis or treatment of humans or other mammals by inhibiting the synthesis of COX-2 enzymes.

Accordingly, the present invention provides a method of inhibiting the synthesis of COX-2 comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. The present invention also provides a method of prophylactic treatment of humans or other mammals by inhibiting the synthesis of COX-2 enzymes.

Thus, in particular, the compounds of the general formula I, or pharmaceutically acceptable salts thereof, are useful for the treatment of excessive or unregulated IL-2, IL-8, and / or IL-8 production by cells of a mammal such as, but not limited to, mononuclear cells and / Or a disease state of a human or other mammal worsened or induced by TNF production.

Thus, in another aspect, the invention provides a method of inhibiting the production of IL-1 in a mammal, comprising administering to the mammal an effective amount of a compound of general formula I, or a pharmaceutically acceptable composition thereof, .

Excessive or uncontrolled IL-1 production is associated with worsening and / or developing the disease. Including acute or chronic pulmonary inflammatory disease states such as rheumatoid arthritis, osteoarthritis, seizures, endotoxemia, and / or inflammatory responses caused by toxic shock, endotoxin or inflammatory bowel disease, Including but not limited to tuberculosis, atherosclerosis, osteoarthritis, multiple sclerosis, cachexia, bone reabsorption, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis . According to recent evidence, IL-1 activity is also associated with diabetes, pancreatic beta cells and Alzheimer's disease.

In another aspect, the invention relates to a method of inhibiting the production of TNF in a mammal, if necessary, comprising administering to the mammal an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.

Excessive or unregulated TNF production may be caused by at least one of the following: rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other joint diseases, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock, adult respiratory distress, Pulmonary fibrosis, pulmonary inflammatory disease, cirrhosis, sarcoisosis, osteoporosis such as osteoporosis, reperfusion injury, host response to transplantation, rejection of other transplantation, muscle pain and heat due to infection such as influenza, AIDS, ARC (AIDS related complications), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis and ulcerative colitis associated with infection or malignant tumors, cachexia similar to AIDS, It is involved in aggravating or mediating many diseases, including pyresis.

Compounds of general formula I are also useful in the treatment of viral infections which are also sensitive to up-regulation by TNF or which will induce TNF production in vivo. Viruses intended for therapeutic use herein are those that are either susceptible to inhibition, such as by TNF inhibition of compounds of general formula I, or produce TNF as a result of infection, either directly or indirectly, such as by reduction of replication. Such viruses include, but are not limited to, HIV-1, HIV-2 and HIV-3, cell spreading viruses (CMV), influenza, adenovirus and viruses Herpes group (Herpes Zoster and Herpes Simplex) , But are not limited to, < / RTI > Accordingly, in another aspect, the invention provides a method of treating a mammal infected with human immunodeficiency virus (HIV), comprising administering to said mammal a compound of general formula I, or a pharmaceutically acceptable salt thereof, .

The compounds of general formula I can also be used in conjunction with veterinary treatment of non-human mammals in need of inhibiting TNF production. TNF mediated diseases for therapeutic or prophylactic treatment in animals include disease conditions such as those mentioned above, particularly viral infections. Examples of such viruses include, but are not limited to, lentiviral infections such as horse infectious anemia virus, chloroplast joint virus, bisnavirus or Medivirus, or feline immunodeficiency virus (FIV), smallpox deficiency or immunodeficiency virus But also retroviruses, or other retroviral infections.

The compounds of the general formula I can also be used for the treatment of inflammatory diseases such as inflammatory diseases such as joint inflammation, eczema, psoriasis and other inflammatory skin diseases such as sunburn, conjunctivitis, pyresis, pain And other diseases associated with inflammation. ≪ RTI ID = 0.0 > [0031] < / RTI >

Compounds of general formula I have also been shown to inhibit the production of IL-8 (interleukin-8, NAP). Thus, in another aspect, the invention provides a method of inhibiting the production of IL-8 in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of general formula I, or a pharmaceutically acceptable salt thereof, .

There are many disease states associated with excessive or unregulated IL-8 production leading to worsening and / or inducing the disease. These diseases are characterized by giant neutrophil infiltration such as psoriasis, inflammatory bowel disease, lebowfusion injury of asthma, heart disease and kidney, adult respiratory distress syndrome, thrombosis and nephrotic syndrome nephropathy It is erased. All of these diseases are associated with increased IL-8 production, which is responsible for neutrophil chemotaxis to the inflamed site. In contrast to other inflammatory cytokines (IL-1, TNF, and IL-6), IL-8 has unique properties that promote neutrophil chemotaxis and activation. Therefore, inhibition of IL-8 production leads to a direct reduction in neutrophil infiltration.

The compounds of general formula I may be administered at an average level, or in some cases below the mean, in a sufficient amount to inhibit the production of cytokines, particularly IL-1, IL-6, IL-8 or TNF, ≪ / RTI > IL-1, IL-6, IL-8 or TNF, for example in the specification of the present invention.

(i) a value of free (unbound) IL-1, IL-6, IL-8 or TNF greater than 1 picogram per ml, (ii) a value associated with IL-1, IL-6, IL-8 or TNF All cells, (iii) the mRNA base value in cells or tissues in which IL-1, IL-6, IL-8 or TNF are present, respectively, in the presence of IL-1, IL-6, IL-

The discovery that compounds of the general formula I are inhibitors of cytokines, in particular IL-1, IL-6, IL-8 and TNF can be found in the production of IL-1, IL-8 and TNF in the in vitro tests described herein On the basis of the efficacy of the compounds of the general formula I.

The term " inhibition of the production of IL-1 (IL-6, IL-8 or TNF) "

a) Excessive in vivo levels of human cytokines (IL-1, IL-6, IL-8 or TNF) by inhibiting the in vivo release of cytokines by all cells including but not limited to monocytes or macrophages Decrease to mean or below average,

b) at the genomic level, downregulating excessive in vivo levels of human cytokines (IL-1, IL-6, IL-8 or TNF)

c) down-regulation by direct synthesis inhibition of cytokines (IL-1, IL-6, IL-8 or TNF)

d) at the level of translation, downregulate excessive in vivo levels of human cytokines (IL-1, IL-6, IL-8 or TNF)

.

As used herein, the term " TNF mediated disease or disease state " refers to a condition in which TNF itself is released by the production of TNF itself or by, for example, IL-1, IL-6 or IL- ≪ / RTI > TNF, < / RTI > Thus, for example, a disease state in which IL-1 is a major component and whose production or activity is exacerbated or hidden in response to TNF is considered a disease state mediated by TNF.

As used herein, the term " cytokine " refers to a secreted polypeptide that is a molecule that affects the function of a cell and modulates intercellular interactions in an immune, inflammatory or blood production response. Cytokines include, but are not limited to, monokines and lymphokines, regardless of which cells produce them. For example, monocaine is generally said to be produced and concealed by single nuclear cells such as macrophages and / or mononuclear cells. However, a number of other cells have also been reported to inhibit the production of monocaine such as natural killer cells, fibroblast, basophil, neurotrophil, endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal, keratinocytes and B- . Lymphokines are generally produced by leukocyte cells. Examples of cytokines include interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor- RTI ID = 0.0 > (TNF-ss). ≪ / RTI >

The term " cytokine inhibition " or " cytokine inhibitory amount ", as used herein, refers to an amount of a cytokine that is exacerbated by excessive or unregulated cytokine production or, when given to a patient to prevent or treat a disease state induced, Refers to an effective amount of a compound of general formula I that will reduce the level to an average or less.

As used herein, the phrase " inhibition of cytokines used for the treatment of HIV-infected humans " refers to (a) the onset and / or maintenance of T cell activation and / or the activation of T cell- / RTI > and / or (b) a cytokine-mediated disease associated with a problem such as a disease state or myositis.

TNF-ss (also known as lymphotoxins) have close structural homology with TNF-a (also known as carcetin), each inducing a similar biological response and binding to the same cell receptor, And TNF- [beta] are all inhibited by the compounds of the present invention and are therefore collectively referred to herein as " TNF " unless specifically stated otherwise in the specification.

In recent laboratories, new members of the MAP kinase family, optionally called CSBP, p38, or RK, have been independently identified. Activation of this novel protein kinase via dual phosphorylation is mediated by a wide range of stimulation spectra such as physico-chemical stress and treatment with lipopolysaccharide or by proinflammatory cytokines such as interleukin-1 and tumor clearance factors, ≪ / RTI > in different cell systems. It has been determined that inhibitors of the present invention, cytokine biosynthesis inhibitors of compounds of general formula I, (II) and (A) are potent and selective inhibitors of CSBP / p. 38 / RK kinase activity. These inhibitors help determine the signaling pathways involved in the inflammatory response. In particular, the first defined signal transduction pathway can be defined as the activity of lipopolysaccharide in cytokine production in macrophages. In addition to the diseases already mentioned, it is also possible to use other agents such as seizures, neurotrauma, reperfusion damage of the heart and kidney, thrombosis, nephritis of the gut-sphere, diabetes mellitus and pancreatic beta cells, multiple tuberculosis, And conjunctivitis.

Next, cytokine inhibitors were tested in several animal models for anti-inflammatory activity. The model system was chosen to be relatively insensitive to cyclooxygenase inhibitors in order to elucidate the intrinsic activity of cytokine inhibitors. Inhibitors have been shown to be effective in many cases in vivo studies. The most prominent is its effect on the collagen-induced arthritis model and inhibition of TNF production in the endotoxin shock model. In the latter study, a reduction in plasma levels of TNF is associated with survival and protection from endotoxin shock associated with death. Also of utmost importance is the effective amount of the compound at the inhibition of aggregate absorption in the iliac vein organ culture system of the rat in rats. (1988) Arthritis Rheum. 31: 1406-1412, Badger, et al., (1989) Circ. Shock 27, 51-61, Votta et al. 15, 533-538, Lee et al., (1993), B Ann. NY Acad., 696, 149-170.

The compounds of formula I and their pharmaceutically acceptable salts will be formulated into pharmaceutical compositions according to the generally accepted standard pharmaceutical practice for use in therapy. Therefore, the present invention also relates to a pharmaceutical composition comprising an effective amount, nontoxic, of a compound of general formula I and a pharmaceutically acceptable carrier or diluent thereof.

The compounds of the general formula I, their pharmaceutically acceptable salts and the pharmaceutical compositions incorporated therein, can be administered by any of the methods usually used for the administration of a drug, for example, orally, topically, parenterally or by inhalation. The compounds of the general formula I can be administered in the customary order in the form of customary preparations prepared by combining the compounds of the general formula I with standard pharmaceutical carriers. It may also be administered by conventional administration methods in combination with a known, second therapeutically active compound. This process may suitably involve mixing, granulating and compressing or dissolving the ingredients according to the desired pharmaceutical preparation. The nature and form of the pharmaceutically acceptable properties or diluents is dictated by the other well known variables and the route of administration and the amount of active ingredient to be combined. The carrier must be " acceptable " in that it can compete with other ingredients of the formulation and is not toxic to the recipient.

The pharmaceutical carrier employed may be, for example, solid or liquid. Examples of solid carriers are lactose, white clay, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of the liquid carrier include syrup, peanut oil, olive oil, water and the like. Likewise, the carrier or diluent may comprise a delaying agent known in the art, such as when the glyceryl mono-stearate or glyceryl distearate is used alone or in combination with a wax.

Various constraint types can be used. Thus, the preparations can be tableted using solid carriers, in the form of powders or pellets, or in the form of tablets or lozenge tablets in hard gelatin capsules. The amount of solid carrier will preferably vary widely from about 25 mg to about 1 g. When liquid carriers are used, the pharmaceutical preparations can be in the form of sterile injectable liquids such as syrups, emulsions, soft gelatine capsules, ampoules or non-aqueous liquid suspensions.

The compounds of the general formula I can be administered locally, which is a non-systemic route of administration. This involves the use of compounds of the general formula I externally in the epidermis or oral cavity, and the method of dripping such compounds in the ear, eye and nose, and not the compound being injected prominently into the bloodstream. In contrast, analgesic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

Formulations suitable for topical administration include liquid or semi-liquid pharmaceutical preparations suitable for penetration of the inflammatory site through the skin, such as a topical drug, lotion, cream, ointment or paste, and suitable for administration to the eye, ear or nose Dropping agent). The active ingredient may contain from 0.001% to 10% w / w, for example from 1% to 2% by weight of the formulation for topical administration. However, it may comprise as much as 10% by weight of the formulation, preferably less than 5% w / w, more preferably between 0.1% and 1% w / w.

Lotions according to the present invention include those suitable for use on the skin or eyes. The lotion used in the eye may optionally contain a sterilizing aqueous solution containing a sterilizing agent and may be prepared by a method similar to that of the preparation method. Lotions or wetting agents used on the skin may also contain an agent such as alcohol or acetone to promote and cool the skin, and / or an oil such as a moisturizer or castor oil or arachis oil such as glycerol.

The cream, ointment or paste according to the present invention is a semi-solid preparation of the active ingredient for external use. They can be prepared by mixing the active ingredient in finely divided form or powder form, alone or in combination with a greasy or free base, with or without the aid of suitable equipment in a suspension of water-soluble, non-aqueous fluids. The base may be selected from the group consisting of hard, soft or liquid paraffin, hydrocarbons such as glycerol, beeswax, metal soap, natural oils such as mucilage, almonds, corn, arachis, castor or olive oil, fats or derivatives thereof or stearic acid or oleic acid Fatty acids may be included with alcohols such as propylene glycol or macrogels. The formulations may incorporate suitable surfactants such as anionic, cationic or nonionic surfactants such as sorbitan esters or polyoxyethylene derivatives thereof. Natural gums, cellulosic derivatives or inorganic substances such as silica gel silica and other ingredients such as lanolin.

The dosage form according to the present invention may contain a bactericidal agent and / or a fungicidal agent and / or a sterile aqueous or oily solution or suspension, preferably comprising a surfactant, And dissolving the active ingredient in a suitable aqueous solution of a suitable preservative. The resulting solution is then filtered and purified, transferred to a suitable sealed container, sterilized by autoclaving or held at 98-100 ° C for half an hour. Alternatively, the solution may be sterilized by filtration and delivered to the container by a preservative treatment technique. Examples of suitable bactericidal and fungicidal bactericides for inclusion in the dosage form are phenylmercuric nitric acid nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for preparing oily solutions include glycerol, dilute alcohol and propylene glycol.

The compounds of the general formula I can be administered parenterally, i. E. Intravenously, intramuscularly, subcutaneously intranasally, rectally, intravaginally or intraperitoneally. Subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for administration thereof can be prepared by conventional techniques. The compounds of general formula I may also be administered by inhalation, i. E. Intranasal and oral inhalation administration methods. Formulations suitable for such dosage regimens, such as aerosol formulations or metered dose inhalers, may be prepared by conventional techniques.

Despite having been disclosed herein for the use of compounds of the general formula I, the oral daily recommended daily dose is preferably about 0.1 to about 80 mg / kg, preferably about 0.2 to 30 mg / kg, Will be about 0.5 to 15 mg. The daily parenteral dosage will be about 0.1 to about 80 mg / kg, preferably about 0.2 to 30 mg / kg, more preferably about 0.5 to 15 mg / kg, of the total weight. The topical daily recommended dose will preferably be from 0.1 to 150 mg daily, from 1 to 4 times, preferably from 2 to 3 times. The daily intake recommended amount will preferably be from about 0.01 mg / kg to about 1 mg / kg per day. The appropriate amount and interval of each of the compounds of formula I and their pharmaceutically acceptable salts will also be determined by the extent and nature of the conditions to be treated, the mode of administration, the route and site of administration, and the particular patient to be treated, It is also known to those skilled in the art that it can be determined by techniques. A number of doses of the compounds of general formula I and their pharmaceutically acceptable salts given daily by day on an appropriate course of treatment, daily doses, can be ascertained by those skilled in the art using routine procedures of treatment determination studies.

The compounds of the new general formula I can also be used in conjunction with veterinary treatment of mammals other than humans in need of inhibition of cytokines. In particular, cytokine mediated diseases for animal therapy include disease states, in particular viral infections, such as those mentioned herein, either therapeutically or prophylactically in the therapeutic treatment sector. Examples of such viruses include, but are not limited to, lentivirus infections such as horse infectious anemia virus, chloroplast joint virus, bisnavirus or Medivirus, or feline immunodeficiency virus (FIV), smallpox deficiency virus or immunodeficiency virus But also retroviruses, or other retroviral infections.

The present invention can not be made due to the limitations of the scope of the present invention, but will be disclosed by reference only to the following illustrative biological examples.

Biological example

The cytokine-inhibitory effect of the compounds of the present invention was determined by the following in vivo test.

≪ Interleukin-1 (IL-1) >

Mononuclear cells of peripheral blood vessels of humans were purified and purified from fresh blood preparations obtained from donor volunteers or from the blood reservoirs of pale yellow-brown membranes according to the reference [Colotta et al, J Immunol, 132, 936 (1984) . These mononuclear cells (1 × 10 ⁶ ) are placed on a 24-well plate at a concentration of 1-2 min / ml per well. Cells were washed gently to remove non-adherent cells and fixed for 2 h. The test compound was then added to the cells for 1 hour before addition of lipopolysaccharide (50 ng / ml) and the cultures were incubated at 37 ° C for an additional 24 hours. At the end of this time the culture supernatant was removed and the cells and all residues were clarified. Next, the culture supernatant is immediately transferred to the culture supernatant as described in Simon et al., J. Immunol. Methods, 84, 85 (1985) (based on the ability of IL-1 to stimulate interleukin 2-producing cell lines (EL-4) to conceal IL-2 in association with A23187 iontransport carriers) The biological activity of IL-1 was tested by the method of Lee et al., J. Immuno Therapy, 6 (1), 1-12 (1990) (ELISA test).

≪ Tumor invasion factor (TNF) >

According to the procedure in Reference [Colotta, R. et al., J Immunol, 132 (2), 936 (1984)], human peripheral blood mononuclear cells were isolated from the pale yellow-brown membrane or platelet ferret residues of blood storage Glass and refined. Mononuclear cells were plated in 24-well multiple dishes at a density of 1 x ¹⁰⁶ cells / ml medium / well. Fresh medium (1 ml, RPMI-1640, Whitaker Biomedical Products, Whitaker, Calif.) Containing penicillin and streptomycin (10 units / ml) together with 1% of calf serum was sucked up and fixed for 1 hour . Cells were incubated in the presence or absence of the test compound in a 1 nM-10 mM dosage range (the compound was dissolved in dimethyl sulfoxide / ethanol and the final solvent concentration in the culture medium was 0.5% dimethylsulfoxide / 0.5% ethanol) Lt; / RTI > Next, lipoic poly bacterial-saccharide (E. coli 055: Sigma Chemical Co., Ltd. Preparation B5 [LPS]) was added and the and culture (100ng / ml in 10ml phosphate buffered saline) in a 37 ℃ 5% CO ₂ incubator 16 Lt; / RTI > for 18 hours. At the end of the incubation period, the culture supernatant was removed from the cells and centrifuged at 3000 rpm to remove cell residues. TNF activity of the supernatant was then tested using the radio-immuno or ELISA test as described in WO 92/10190 and Becker et al., J Immunol, 1991, 147, 4307.

IL-1 and TNF inhibitory activities do not appear to correlate with the properties of compounds of general formula I that modulate arachidonic acid metabolism inhibition. Furthermore, the ability to inhibit the production of prostaglandins and / or the synthesis of rucotrienes by non-steroidal anti-inflammatory drugs in combination with potential cyclooxygenase and / or lipoxygenase inhibitory activity is essential for the non-toxic administration of the compounds TNF or < RTI ID = 0.0 > IL-1. ≪ / RTI >

≪ In vivo TNF test >

While the observed test is ex vivo, compounds of general formula I may also be tested in vivo systems as described in the following references:

(1) "Differentiation In Vivo of Classical Non-Steroidal Antiinflammatory Drugs from Cytokine Suppressive Antiinflammatory Drugs and Other Pharmacological Classes Using Mouse Tumor Necrosis Factor Alpha Production", Grisword et al., Drugs Under Exp. and Clinical Res., XIX (6), 243-248 (1993); or

(2) Boehm, et al., 1-substituted 4-aryl-5-pyridinylimidazole-a new class of cytokine suppressive drugs with low 5-lipoxygenase and cyclooxygenase inhibitory potency. Journal of Medicinal Chemistry 39, 3929-3937 (1996), the entire contents of which are incorporated herein by reference.

Using the above test, representative compounds of the general formula I, Examples 1 to 6, 11, 12, 16, 17, 20 to 26 and 31 showed a positive inhibitory activity of less than 50 uM in this test.

≪ Interleukin-8 (IL-8) >

The endothelial cells (HUVEC) (cell system, Kirand, and wa) of the first human umbilical cord conduit were cultured in culture medium supplemented with 15% calf serum and 1% CS-HBGF consisting of aFGF and heparin Respectively. Cells were then diluted 20-fold before plating (250 ul) and the 96-well plates were covered with gelatin. Prior to use, the culture medium was replaced with fresh medium (200 ul). Next, buffer or test compound (between 25 uL and 1 to 10 uM concentration) was added to each of four wells of wells and the plate was incubated for 6 hours in a humid incubator at 37 ° C under a pressure of 5% CO ₂ . The supernatant was removed at the end of the incubator and the IL-8 concentration was tested using an IL-8 ELISA kit obtained from the R & D system (Minepolis, MN). All data are expressed as the mean value (ng / ml) of multiple samples based on a standard curve. The appropriate IC ₅₀ 's is calculated by nonlinear regression analysis.

<Test for cytokine-specific binding protein>

Binding tests of radiated competition were developed to provide a highly reproducible primary screen for structure-activity studies. This test provides many advantages over conventional biological assays using freshly liberated human mononuclear cells as the source of cytokines and quantifies them by ELISA tests. In addition to more easy testing, it has been extensively confirmed that binding studies are highly correlated with the results of biological quantification. Specific and regenerable cytokine inhibitor binding studies were developed using soluble cystosolic moieties from THP.1 cells and compounds identified as radioactive isotopes. U.S. Ser. No. 08 / 311,755, filed by Lee et al. In September 1993, which is incorporated herein by reference in its entirety, PCT No. 94/10529 filed by Lee et al. On Sep. 16, 1994, Nature 300, n (72), 739-746 (December 1994) describes such a method in which screening agents interact to identify compounds bound to cytokine-specific binding proteins (hereinafter referred to as CSBP). However, for purposes of this disclosure, a binding protein may be in solution in a free form or in a fixed form, and may also be genetically engineered to be expressed on the surface of a recombinant host cell, such as a phage display system or fusion protein. Alternatively, cytosolic portions or whole cells containing CSBP can be used in a screening protocol. Regardless of the form of protein binding, a plurality of compounds can be contacted with the binding protein under conditions sufficient to form the compound / binding protein complex and compounds capable of making, enhancing or interfering with the complex can be detected.

Representative final compounds of the formula I, Examples 1 to 6, 11, 17, 20 to 31 all exhibit a positive inhibitory activity of less than 50 uM in this binding assay.

CSBP kinase analysis

This test measures the CSBP-catalytic transfer of ³² P from [a- ³² P] ATP to threonine residues in an epithelial growth factor receptor (EGFR) -induced peptide (T669) with the following sequence: KRELVELTPSGEAPNQALLR Water 661-681) (see Gallagher et al., &Quot; Regulation of Stress Induced Cytokine Production by Pyridinyl Imidazoles: Inhibition of CSBP Kinase &quot;, Bio Organic & Medicinal Chemistry,

The kinase reaction (total volume 30 ul) contained: 25 mM HEPES buffer, pH 7.5, 10 mM MgCl ₂ , 170 uM ATP ⁽¹⁾ , 10 uM Na orthovanadate, 0.4 mM T669 peptide, and yeast- CSBP2 20-80 ng (see Lee et al., Nature 300, n (72), 739-746 (Dec. 1994).) The compound (5 ul from [6X] stock ⁽²⁾ ) was reacted with 32P / MgATP Pre-incubation with enzymes and peptides for 20 minutes on ice prior to start-up The reaction was incubated for 10 minutes at 30 ° C and stopped by the addition of 10 μl of 0.3M phosphoric acid 32P-labeled peptides were incubated with phospho-cellulose (Wattsman, 81 The filter was washed three times with 75 mM phosphoric acid, washed twice with H ₂ O and treated as 32P.

(1) The Km of the CSBP for ATP was determined to be 170 uM. The compounds were therefore screened at the Km value of ATP.

(2) The compounds were generally dissolved in DMSO and diluted in 25 mM HEPES buffer to give a final concentration of 0.17% DMSO.

Representative compounds of the general formula I, Examples 1 to 19, 30 and 31 all exhibit a positive inhibitory activity of the IC ₅₀ of less than ₅₀ uM in this binding assay.

&Lt; Prostoglandan endoperoxidase Synthase-2 (PGH-2) test >

The following test describes a method for determining the inhibitory effect of a compound of general formula I on human PGHS-2 protein expression in LPS-stimulated human mononuclear cells.

Methods: Human peripheral blood mononuclear cells were separated from the soft membranes by centrifugation through Ficoll and Percoll gradients. Cells were seeded in plates with 24 wells at 2 x 10 ⁶ cells per well and allowed to adhere to RPMI supplemented with 1% human AB serum, 20 mM L-glutamine, penicillin-streptomycin and 10 mM HEPES for 1 hour. The compounds were added at various concentrations and incubated at 37 ° C for 10 minutes. LPS was added at 50 ng / well (to induce enzyme expression) and incubated overnight at 37 ° C. The supernatant was removed and the cells were washed once in cold PBS. The cells were washed with 100 μL of low temperature lysis buffer (50 mM Tris / HCl pH 7.5, 150 mM NaCl, 1% NP40, 0.5% sodium deoxycholate, 0.1% SDS, 300 μg / mL DNAse, 0.1% Triton X-100, 1 mM PMSF, Leupeptin, 1 mM pepstatin). The lysate was centrifuged (10,000 x g for 10 minutes, 4 degrees Celsius) to remove residues and the soluble fraction was subjected to SDS PAGE analysis (12% gel). Proteins separated on the gel were transferred onto a nitrocellulose membrane by electrophoresis at 60 volts for 2 hours. The membrane was pretreated in PBS / 0.1% Tween 20 with 5% nonfat dry milk for 1 hour. After three washes in PBS / Tween buffer, a 1: 2000 dilution of monospecific antiserum versus PGHS-2 or 1: 1000 dilution of antiserum versus PGHs-1 was performed for 1 hour in PBS / Tween with 1% BSA And cultured with stirring. The membranes were washed three times in PBS / Tween and incubated for 1 hour in PBS / Tween with 1% BSA in a 1: 3000 dilution of donkey antiserum versus rabbit Ig anti-serum (Amersham) And cultured with stirring. The membrane was then washed three times in PBS / Tween and the degree of expression of prostaglandin endoperoxidase synthase-2 was detected using an ECL Immuno Detection System (Amersham).

Results: The following compounds were determined to be active in this assay (i. E., Inhibited LPS-induced PGHS-2 protein expression to the same extent as to inhibit cytokine production as indicated in the indicated assays): 4 - (4-fluorophenyl) -2- (4-methylsulfinylphenyl) -5- (4-pyridyl) imidazole; 6- (4-fluorophenyl) -2,3-dihydro-5- (4-pyridyl) imidazole [2,1-b] thiazole; And dexamethasone

Several compounds were measured and found to be inactive (less than 10 μM): 2- (4-methylsulfinylphenyl) -3- (4-pyridyl) -6,7-dihydro- (5H) -pyrrolo [ , &Lt; / RTI &gt; 2-a] imidazole; Pennidone and NDGA. The compounds measured showed that in the same experiment, PGHS-1 or cPLA₂ But did not inhibit the protein level.

TNF-α Traumatic Brain Injury Test

This assay allows the mice to experimentally induce lateral fluid-shock traumatic brain injury (TBI) and then examine the expression of tumor necrosis within a particular brain region. Adult Sprague-Dawley rats (n = 42) were anesthetized with sodium pentobarbital (60 mg / kg, ip) and a moderate (2.4 atm) lateral fluid-shock brain injury Or " sham " treatment (no anesthesia and surgery without damage, n = 18). The animals were sacrificed at 1, 6, and 24 hours post-injury, and the brain was removed, and the left cortex (LC), the corresponding region in the opposite cortex (RC) (RA), left hippocampus (LH), and right hippocampus (RH) tissue samples were prepared. Total RNA is isolated and Northern blot hybridization is performed and pooled against TNF- [alpha] positive control RNA (macrophage = 100%). LH (104 ± 17% in positive control, p <0.05 in comparison with Siam), LC (105 ± 21%, p <0.05) and LA (69 ± 8% , p <0.01), the expression of TNF-α mRNA was significantly increased. In addition, the increase of TNF-α mRNA expression was observed in 6 hours after injury (46 ± 8%, p <0.05), LC (30 ± 3%, p <0.01) 0.01), but not at 24 hours after injury. In the contralateral hemisphere, expression of TNF-α mRNA was increased in the RH (46 ± 2%, p <0.01), RC (4 ± 3%) and RA (28 ± 11%), RC (7 ± 5%) and RA (26 ± 6%, P <0.05) in the second group, but not in the 24th group. In the case of Siam (untreated surgery) or untreated animals, no consistent change in TNF-α mRNA expression is observed in any of the six brain regions at any time in any hemisphere. This result indicates that the transient expression of the following fluid-shock brain injury, TNF-a mRNA, is altered in the specific brain region including the non-traumatic hemisphere. Since the TNF- [alpha] can induce nerve growth factor (NGF) and release other cytokines from activated astrocytes, the post-injury alteration in gene expression of TNF- [alpha] is associated with both rapid and regenerative responses to CNS trauma .

CNS damage model for IL-β mRNA

This analysis characterizes the partial expression of interleukin-l [beta] (IL-l [beta]) mRNA in specific brain regions after lateral fluid-shock traumatic brain injury (TBI) in mice experimentally. Adult Sprague-Dawley rats (n = 42) were anesthetized with sodium pentobarbital (60 mg / kg, ip) and a moderate (2.4 atm) lateral fluid-shock brain injury Or " sham " treatment (no anesthesia and surgery without damage, n = 18). The animals were sacrificed at 1, 6, and 24 hours post-injury, and the brain was removed, and the left cortex (LC), the corresponding region in the opposite cortex (RC) (RA), left hippocampus (LH), and right hippocampus (RH) tissue samples were prepared. Total RNA was isolated and Northern blot hybridization was performed and the amount of brain tissue IL-1 [beta] mRNA was expressed as a percentage of the radioactivity of IL-1 [beta] positive macrophage RNA placed on the same gel. At 1 hour after brain injury, the LC (20.0 ± 0.7%, n = 6, p <0.05 compared with Siamese), LH (24.5 ± 0.9%, p <0.05) The expression of IL-1β mRNA was markedly increased in LA (21.5 ± 3.1%, p <0.05) and LC (4.0 ± 0.4%, n = 6, p <0.05) LH (5.0 +/- 1.3%, p < 0.05). In the case of TIA or inexperienced animals, no expression of IL-1 beta mRNA is observed anywhere in each brain region. This result indicates that the expression of the following TBI, transient IL-1 [beta] mRNA, is partially stimulated in specific brain regions. This partial alteration of cytokines such as IL-1 [beta] plays an important role in pathological or regenerative sequelae following damage to the brain damage.

Synthesis Example

The invention will now be described on the basis of the following examples, which are merely illustrative and are not to be construed as limiting the scope of the invention. Unless otherwise indicated, all temperatures are in degrees Celsius, all solvents are of high purity, and all reactions proceed anhydrous within the argon atmosphere.

In an embodiment, all temperatures are in degrees Celsius. Unless otherwise indicated, mass spectra were obtained using a VG Zab mass spectrometer using fast atom bombardment or a fine mass platform of cationic mode using 95: 5 CH ₃ CN / CH ₃ OH with 1% formic acid as carrier solvent. Electrospray ionization Mass spectrometer. ¹ H-NMR (hereinafter "NMR") spectrum was recorded at 250 MHz using a Bruker AM 250 or Am 400 spectrometer. The multiplicity shown is: s = singlet, d = doublet, t = triplet, q = quadruplet, m = multiple and br is a broad signal. Sat is the saturated solution, and eq is the molecular equivalence ratio of the reagent to the main reactant.

Moment chromatography is carried out on Merck Silica gel 60 (230-400 mesh).

&Lt; Example 1 >

4- (4-fluorophenyl) -5- (2-phenoxypyrimidin-4-yl) imidazole

a) 2-Methylthiopyrimidine-4-carboxaldehyde Dimethyl acetal

(60 mL, 459 mmol) and N, N-dimethylformaldehyde dimethyl acetal (60 mL, 459 mmol) were mixed together at 100 DEG C for 18 hours. The mixture was cooled.

Methanol (300 mL), thiourea (69.6 g) and sodium methoxide (231 mL, 25 wt% in MeOH) were added to the mixture and stirred at 70 ° C for 2 hours. After cooling, iodomethane (144 mL) was added dropwise and the mixture was stirred at room temperature for 3 hours. After diluting with EtOAc and water, The organic phase was separated and concentrated order to obtain the compound of the above title was dried (Na ₂ SO ₄₎ as a brown oil (75.5g, 82% yield). _{^{1 H NMR (CDCl 3):}} d 8.17 (d, 1H), 6.77 (d, 1H), 5.15 (s, 1H), 3.40 (s, 6H).

b) 2-Methylthiopyrimidine-4-carboxaldehyde

The product of Example 1 (a) (9.96 g, 50 mmol) and 3N HCl (42 mL, 126 mmol) were combined and stirred at 48 ° C for 16 h, cooled to 23 ° C and combined with EtOAc (200 mL) ₂ CO ₃ (12.6 g, 150 mmol). The aqueous phase was extracted with EtOAc (4 x 150 mL, dried (Na ₂ SO ₄ )) and concentrated and the residue was filtered through a silica pad (ca 150 mL) with CH ₂ Cl ₂ to give 7.49 g (97% Compound. ¹ H-NMR (CDCl ₃ ):? 9.96 (s, 1), 8.77 (d, 1), 7.44 (d, 1), 2.62 (s, 3).

c) 1-t-Butoxycarbonyl-4-aminopiperidine

(39.9 g, 0.20 mol), THF (150 mL), H ₂ O (300 mL) and H ₂ NOH (300 mL) were added to a solution of 1-t-butoxycarbonyl-4-aminopiperidin- HCl (55.2, 0.80 mol) was dissolved together and a small amount of Na ₂ CO ₃ (55.2 g, 0.53 mol) was added. The mixture was stirred at 23 &lt; 0 &gt; C for 14 hours to evaporate most THF in vacuo, adjusted to pH> 10 with 50% aqueous NaOH, extracted with EtOAc (5 x 50 mL) and then concentrated to a white foam. Trituration with hexane, filtration and drying of the solid in vacuo afforded 40.31 g.

The residue was dissolved in EtOH (absolute) (1 L) and Raney Ni (slurry in 50 mL EtOH) was added and the mixture was reduced under H ₂ (50 psi) for 3.5 h. The catalyst was filtered off and washed with EtOH.

Concentrate to give 38.44 g (96% overall) of the title compound as a colorless oil that solidifies on a white solid upon placing at -20 [deg.] C.

d) 2-Methylthiopyrimidine-4-carboxaldehyde [1-t-butoxycarbonyl-4-aminopiperidine]

A mixture of the product of the previous step (6.51 g, 32.6 mmol), MgSO ₄ (ca 2 g), the product of Example 1 (b) (4.84 g, 31.4 mmol) and CH ₂ CL ₂ (100 mL) Lt; / RTI &gt; Filtration and concentration of the filtrate gave the title compound as a yellow oil. _{H-NMR (CDCl 3):} δ 8.57 (d, 1), 8.27 (s, 1), 7.58 (d, 1), 4.05 (m, 2), 3.55 (m, 1), 3.00 (m, 2) , 2.60 (s, 3), 1.75 (m, 4), 1.48 (s, 9).

e) 4-Fluorophenyl-tolylsulfonomethylformamide

To the suspension of p-toluenesulfate (30 g) in H ₂ O (100 mL) was added methyl t-butyl ether (50 mL) followed by the addition of concentrated HCl (15 mL) dropwise. After stirring for 5 min, the organic phase was removed and the aqueous phase was extracted with methyl t-butyl ether. The organic phase was dried (Na ₂ SO ₄ ) and concentrated to near dryness. Hexane was added and the precipitate was collected to give p-toluenesulfinic acid; Yield 22 g. A mixture of p-toluenesulfinic acid (22 g, 140.6 mmol), p-fluorobenzaldehyde (22 mL, 206 mmol), formamide (20 mL, 503 mmol) and camphorsulfonic acid (4 g, 17.3 mmol) Lt; / RTI &gt; The solid was triturated and stirred with a mixture of MeOH (35 mL) and hexane (82 mL) and then filtered. The solid was suspended again in MeOH / hexane (1: 3, 200 mL) and stirred vigorously to allow the remaining mass to be crushed. To give a compound of the title by filtration (27g, yield ^{62%): 1 H NMR (} 400MHz, CDCl 3) d 8.13 (s, 1H), 7.71 (d, 2H), 7.43 (dd, 2H), 7.32 ( d, 2H), 7.08 (t, 2H), 6.34 (d, 1H), 2.45 (s, 3H).

f) 4-Fluorophenyl-tolylsulfonomethylisocyanide

4-Fluorophenyl-tolylsulfonomethylformamide (2.01 g, 6.25 mmol) in DME (32 mL) was cooled to -10 degrees Celsius. POCl ₃ (1.52 mL, 16.3 mmol) was added followed by dropwise addition of triethylamine (4.6 mL, 32.6 mmol) in DME (3 mL) with an internal temperature kept below -5 degrees Celsius. The mixture was slowly warmed to ambient temperature for 1 hour, poured into H ₂ O and extracted with EtOH. The organic phase was washed with saturated aqueous NaHCO ₃ , dried (Na ₂ CO ₃ ) and concentrated. Grinding the residue with petroleum ether and filtered to yield the compound of the title (1.7g, yield ^{90%): 1 H NMR (} CDCl 3) d 7.63 (d, 2H), 7.33 (m, 4H), 7.10 (t , 2H), 5.60 (s, IH), 2.50 (s, 3H).

g) Preparation of 1 - [(1-t-butoxycarbonyl) piperidin-4-yl] -4- (4- fluorophenyl) Imidazole

The product of Example 1 (d) and the product of the previous example (9.41 g, 32.6 mmol), DMF (64 mL) and K ₂ CO ₃ (4.43 g, 32.4 mmol) were combined and stirred for 2 days and diluted with Et ₂ O Followed by filtration. Wash the solids with Et ₂ O and the filtrate was concentrated to a yellow solid. The solid was triturated with Et ₂ O, filtered, washed with additional Et ₂ O and then dried in vacuo to give 9.07 g of the title compound as a white solid (62% yield from the product of Example 1 (b) )). MS ES + m / z = 470 (MH ^&lt; ⁺ & gt ^; ).

h) Preparation of 1 - [(1-t-butoxycarbonyl) piperidin-4-yl] -4- (4- fluorophenyl) -5 - [(2-methylsulfonyl (pyrimidin- )] Imidazole

Of OXONE (28.5g, 46.4mmol) in the exemplary embodiment the former dissolved in THF product (9.07g, 19.3mmol) to -10 degrees Celsius, cooled, and H ₂ O (250mL) was added dropwise. The mixture was stirred at 23 [deg.] C for 24 hours, combined with ice (100 mL) and CH ₂ Cl ₂ (700 mL) and the aqueous phase separated. The organic phase was washed with brine (100 mL), dried (Na ₂ SO ₄ ), concentrated and dried in vacuo to give 8.27 g (85%) of the title compound as a white foam. MS ES + m / z = 502 (MH ^&lt; ⁺ & gt ^; ).

i) 1 - [(1-t-Butoxycarbonyl) piperidin-4-yl] -4- (4- fluorophenyl) -5 - [(2- phenoxypyrimidin- Imidazole

NaH (60% in mineral oil) (1.6 g, 40 mmol) was washed with dry THF and layered with THF (75 mL) followed by phenol (4.14 g, 44 mmol) in solid form. After precipitating in vigorous reaction for 5 minutes, the product of the previous example (5.01 g, 10 mmol) was added portionwise, reacted with stirring for 90 minutes, concentrated in vacuo and the residue was dissolved in CH ₂ Cl ₂ (300 mL) The residue was washed with 10% aqueous NaOH (2 x) and dried (Na ₂ SO ₄ ) and filtered through a silica gel pad with 0-2% MeOH in CH ₂ Cl ₂ , the desired fractions were concentrated and the residue dissolved in acetone / To give 2.79 g (54%) of the title compound. MS ES + m / z = 502 (MH ^&lt; ⁺ & gt ^; ).

j) 1- (4-Piperidinyl) -4- (4-fluorophenyl) -5- (2- phenoxypyrimidin-

The product of the previous example (3.91 g, 7.59 mmol) was combined with cold TFA (75 mL) then stirred at 23 ° C for 15 min, the reaction was concentrated in vacuo and the residue was dissolved in EtOAc (200 mL) Washed with an aqueous NaOH solution (2 x 100 mL), dried (Na ₂ SO ₄ ), concentrated and the residue crystallized from acetone / hexane to give 2.24 g (71%) of the title compound as white crystals. mp = 182 to 183 degrees Celsius.

&Lt; Example 2 >

4- (4-fluorophenyl) -5- (2-phenoxy-4-pyridinyl) imidazole

a) 2-Chloro-4-hydroxymethylpyridine

2-Chloro-4-pyridinecarboxylic acid (12.9 g, 82.1 mmol) was added portionwise to a suspension of NaBH ₄ (4.66 g, 123 mmol) in THF (400 mL) at 0 ° C. The solution was warmed to room temperature and stirred for 1.5 h, then a solution of BF ₃ O (Et) _{2 in} THF (125 mL) was added over 3 h. The mixture was further stirred at room temperature for 20 hours, cooled to 0 DEG C and 1.5N HCl (100 mL) was added dropwise. The temperature was raised to room temperature, the THF was deprotonated and the pH was adjusted to 10-11 by addition of 4N NaOH solution. The solution was extracted three times with EtOAc and the organic layer was washed with saturated NaCl solution. The organic layer was combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (10.8 g, yield 92%) as a white solid. _{^{1 H NMR (CDCl 3):}} δ 8.30 (d, 1H, J = 4.9Hz), 7.37 (s, 1H), 7.22 (d, 1H, J = 4.9Hz), 4.76 (s, 2H), 2.50 (br -s, 1 H).

b) 2-Chloro-4-pyridinecarboxaldehyde

A suspension of 2-chloro-4-hydroxymethylpyridine (8.0 g, 55.9 mmol), NBS (14.9 g, 83.9 mmol) and K ₂ CO ₃ (11.75 g, 97.1 mmol) in ethyl acetate was refluxed for 3 hours. Other NBS (14.9 g, 83.9 mmol) and Na ₂ CO ₃ (12.0 g, 114 mmol) were added and heating continued for 3.5 h. The reaction mixture was cooled and our filtered through a pad of celite and concentrated and purified by 0.5 to _{4% CH 3 OH / CH 2} Cl 2 under reduced pressure. The combined fractions were washed with (saturated) NaHCO ₃ , 10% Na ₂ S ₂ O ₃ and (saturated) NaCl, dried, filtered and evaporated to give the title compound as a pale yellow solid (5.3 g, ). ¹ H NMR (CDCl ₃ ):? 10.06 (s, 1H), 8.66 (d, 1H, J = 5.0 Hz), 7.76 (s, 1H), 7.66 (d, 1H, J = 5.0 Hz).

c) 2-Chloro-4-pyridinecarboxyaldehyde (1-t-butoxycarbonyl-4-aminopiperidine)

The title compound was obtained using the procedure of Example 1 (d), except 2-chloro-4-pyrimidinecarboxaldehyde was used. ¹ H NMR (CDCl ₃ ):? 8.45 (d, IH, J = 5.1 Hz), 8.29 (s, IH), 7.65 2H), 3.48 (m, 1H), 3.03 (m, 2H), 1.73 (m, 4H), 1.48 (s, 9H).

d) 1- (1-t-Butoxycarbonyl-4-piperidinyl) -4- (4- fluorophenyl)

Purification by an instant chromatography with 0-5% CH ₃ OH / CH ₂ Cl ₂ following the procedure of Example 1 (g), except that the compound from the previous step was used and then recrystallized from ethyl acetate / To give the title compound as a pale yellow solid.

e) 1- (1-t-Butoxycarbonyl-4-piperidinyl) -4- (4-fluorophenyl)

To a stirred suspension of NaH (120 mg, 3.0 mmol) in DMA (1.3 mL) was added phenol (0.40 g, 4.25 mmol). After the bubbling was completed, 1- (1-t-butoxycarbonyl-4-piperidinyl) -4- (4-fluorophenyl) -5- g, 0.44 mmol) and the solution was heated at 120 [deg.] C until no evidence of presence of the starting material was present by mass spectrometry. To the cooled solution was added 1 M NaOH and the mixture was extracted three times with EtOAc. The combined organic layers were washed with (saturated) NaCl, dried with magnesium sulfate, filtered and evaporated under reduced pressure to give a pale yellow solid. The solid was then chromatographed with 50-80% EtOAc / hexanes to give the title compound as a white solid (143 mg, 64% yield). ES (+) MS m / e = 515 (MH ^&lt; ⁺ & gt ^; ).

f) 1- (4-Piperidinyl) -4- (4-fluorophenyl) -5- (2- phenoxy-4-pyridinyl) imidazole

To the compound of the previous step (143 mg, 0.28 mmol) was added TFA solution (10 mL) cooled at -10 degrees Celsius. The reaction temperature was raised to room temperature, stirred at room temperature for 30 minutes, then evaporated under reduced pressure to give an orange oil which was dissolved in water (10 mL) and 3N HCl (0.5 mL) was added. The water layer was washed twice with EtOAc and basified with 50% NaOH, then the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with NaCl, dried with magnesium sulfate, filtered and evaporated under reduced pressure to give a white foam (80 mg, 70%). ES (+) MS m / e = 415 (MH ^&lt; ⁺ & gt ^; ).

&Lt; Example 3 >

4- (4-fluorophenyl) -5- (2- (4-methoxyphenoxy) -4-pyridinyl) imidazole

The title compound was obtained in two steps as a white foam in 74% yield following the procedure of Example 2e and 2f but using 4-methoxyphenol. ES (+) MS m / e = 445 (MH ^&lt; ⁺ & gt ^; ).

<Example 4>

4- (4-fluorophenyl) -5- (2- (4-fluorophenoxy) -4-pyridinyl) imidazole

The title compound was obtained in two steps as a white foam in 35% yield following the procedure of Example 2e and 2f but using 4-fluorophenol. ES (+) MS m / e = 433 (MH ^&lt; ⁺ & gt ^; ).

&Lt; Example 5 >

4- (4-fluorophenyl) -5- [2- (4-methoxyphenoxy) pyrimidin-4-yl]

The title compound was prepared using the method of Example 1 (i) and 1 (j) except 4-methoxyphenol was used. mp = 190-191 degrees Celsius.

&Lt; Example 6 >

4- (4-fluorophenyl) -5- [2- (4-fluorophenoxy) pyrimidin-4-yl]

The title compound was prepared using the method of Example 1 (i) and 1 (j) except 4-fluorophenol was used. mp = 186 to 187 degrees Celsius.

&Lt; Example 7 >

4- (4-fluorophenyl) -5- [2- (4-aminocarbonylphenoxy) pyrimidin-4-yl]

The title compound was prepared using the method of Example 1 (i) and 1 (j) except 4-hydroxybenzamide was used. mp = 229 to 230 degrees Celsius.

&Lt; Example 8 >

4- (4-fluorophenyl) -5- [2- (4-ethylphenoxy) pyrimidin-4-yl]

The title compound was prepared using the method of Example 1 (i) and 1 (j) except 4-ethylphenol was used. mp = 173-174 degrees Celsius.

&Lt; Example 9 >

4- (4-fluorophenyl) -5- [2- (4-benzyloxyphenoxy) pyrimidin-4- yl] imidazole

The title compound was prepared using the method of Example 1 (i) and 1 (j) except 4-benzyloxyphenol was used. mp = 178-179 degrees Celsius.

&Lt; Example 10 >

4- (4-fluorophenyl) -5- [2- (4-cyanophenoxy) pyrimidin-4-yl]

The title compound was prepared using the method of Example 1 (i) and 1 (j) except 4-cyanophenol was used. mp = 192 to 193 degrees Celsius.

&Lt; Example 11 >

4- (4-fluorophenyl) -5- [2- (4-hydroxyphenoxy) pyrimidin-4-yl]

The title compound was prepared using the method of Example 1 (i) and 1 (j) except that hydroquinone was used. mp = 255 to 260 degrees Celsius.

&Lt; Example 12 >

(4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5- [2- (4- phenoxy) pyrimidin-

a) 1-Amino-4- (1,3-dioxycyclopentyl) cyclohexane

Sodium carbonate (49.2 g, 547 mmol) was added portionwise to a mixture of 1,4-cyclohexanedione monoethylene ketal (27.6 g, 177 mmol) and hydroxyamine hydrochloride (49.2 g, 708 mmol) in water (250 mL). After stirring for 1 h, the mixture was extracted with EtOAc. The organic phase was dried (sodium sulfate) and concentrated to give 4-91,3-dioxycyclopentyl) -cyclohexanone oxime (27.5 g, 90% yield).

The oxime (27.5 g, 161 mmol), Raney Ni (ca 13.5 mL as a suspension in EtOH) and EtOH (200 mL) were combined and shaken at 50 psi for 4 hours. The catalyst was filtered off and the filtrate was concentrated to give the title compound (23.6 g, 93% yield) as a colorless oil. _{^{1 H NMR (CDCl 3):}} δ 2.64 (m, 1H), 1.75-1.25 (m, 12H).

b) Preparation of 2-methylthiopyrimidine-4-carboxaldehyde (4-ethylene ketalcyclohexyl) imine

Methylthiopyrimidine-4-carboxaldehyde (9.5 g, 6.9 mmol) prepared in Example 1 (b) and 1-amino-4- (1,3-dioxycyclopentyl) cyclo Hexane (10.8 g, 6.9 mmol) in DMF (150 mL) was stirred for 18 hours. The title compound was used without any purification method. _{^{1 H NMR (CDCl 3):}} δ 8.51 (d, 1H), 8.21 (s, 1H), 7.53 (d, 1H), 3.93 (s, 4H), 3.40 (m, 1H), 2.55 (s, 3H) , 1.94 - 1.70 (m, 6H), 1.61 (m, 2H).

c) Preparation of 1- (4-ethylenecetacyclohexyl) imidazole-4- (4-fluorophenyl) -5 - [(2- methylthio) pyrimidin-

Fluorophenyl-norylsulfonomethylisocyanide (26 g, 90 mmol) and potassium carbonate (15.7 g, 90 mmol) prepared in Example 1 (f) were added to the crude product from the previous example in DMF cooled to 0 deg. 113.6 mmol). The mixture was stirred at 0 ° C for 3 hours, then slowly warmed to room temperature and stirred for 18 hours. EtOH was added and the solid was washed with EtOAc and the mixture was filtered. Water was added to the filtrate and the organic phase was separated, dried (sodium sulfate) and concentrated. The mixture was evaporated to near dryness and washed with 1: 1 EtOAc / to give the title compound as pale yellow crystals. _{^{1 H NMR (CDCl 3):}} δ 8.33 (d, 1H), 7.81 (s, 1H), 7.43 (q, 2H), 7.12 (t, 2H), 6.78 (d, 1H), 4.74 (m, 1H) (Dd, 2H), 4.00 (s, 4H), 2.59 (s, 3H), 2.18 (dd, 2H), 2.04 (dq, 2H), 1.89

d) Preparation of 1- (4-ethylenecetacyclohexyl) -4- (4-fluorophenyl) -5 - [(2-methylsulfoxy) pyrimidin-

Oxone (0.36 g, 56 mmol) dissolved in water (2 mL) was added to a solution of the compound from the previous step in THF (2 mL) and methanol (2 mL) at 0 degrees Celsius. The mixture was stirred for 5 hours, then poured into 10% sodium hydroxide and then extracted with EtOAc. The organic phase was dried (sodium sulfate), concentrated. Grinding the residue with Et ₂ O and filtered to obtain the compound of the title as a white solid (0.089g, yield 45%). _{^{1 H NMR (CDCl 3):}} δ 8.36 (d, 1H), 7.82 (s, 1H), 7.42 (q, 2H), 7.02 (t, 2H), 6.79 (d, 1H), 4.80 (m, 1H) , 4.00 (s, 3H), 2.20 (m, 2H), 2.06 (m, 3H), 1.89 (m, 2H), 1.70 (m, 5H).

e) Preparation of 1- (4-ethylenecetacyclohexyl) -4- (4-fluorophenyl) -5 - [(2- phenoxy) pyrimidin-

To a suspension of sodium hydride (0.18 g, 4.6 mmol) in dry THF (6 mL) was added phenol (0.43 g, 4.6 mmol). When gas evolution ceased, the previous sulfoxide (0.242 g, 2.3 mmol) was added and the mixture was stirred overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried (sodium sulfate) and concentrated. The residue was triturated with ethyl acetate / hexane to give the title compound (0.628 g, 57% yield) as a white solid. _{^{1 H NMR (CDCl 3):}} d 8.40 (d, 1H), 7.97 (s, 1H), 7.45 (m, 4H), 7.27 (m, 3H), 7.04 (t, 2H), 6.85 (d, 1H) , 4.57 (m, 1H), 3.99 (t, 4H), 1.89 (m, 4H), 1.72 (d, 2H), 1.43 (m, 2H).

f) Preparation of 1- (4-oxocyclohexyl) -4- (4-fluorophenyl) -5 - [(2- phenoxy) pyrimidin-

A mixture of the compound from the previous step (0.628 g, 1.3 mmol) in 3N HCl (6 mL) was stirred for 36 h, then neutralized with a saturated aqueous sodium carbonate solution and filtered. The solids were washed with water and the aqueous mixture was extracted with ethyl acetate. The organic phase was dried (sodium sulfate) and concentrated to give the title compound as a lower crystal (0.439 g, 79%). IR (neat) 1717, 1570, 1506. 1 H NMR (CDCl 3) 8.41 (d, 1H), 7.72 (s, 1H), 7.46 (m, 4H), 7.29 (m, 3H), 7.08 (t, 2H ), 6.90 (d, IH), 5.09 (m, IH), 2.37 (dd, 2H), 2.24 (m, 2H), 2.15 (dt, 2H), 2.02 (dq, 2H).

g) Preparation of trans -1- (4-hydroxycyclohexyl) imidazole-4- (4-fluorophenyl) -5 - [(2- phenoxy) pyrimidin-

To a solution of the compound of the example (0.439 g, 1.03 mmol) in methanol / THF (1 mL, 1: 1) was added NaBH ₄ solution (1 mL 1 M solution, 1.52 g NaBH ₄ , methanol (30 mL) and 25% NaOMe ) Was added. After stirring for 30 minutes, the mixture was quenched with saturated sodium carbonate and the solvent was evaporated. The residue was recrystallized from methanol / water to give the title compound (0.275 g, 64% yield) as white needles crystals. _{^{1 H NMR (CDCl 3):}} 8.40 (d, 1H), 7.70 (s, 1H), 7.44 (m, 4H), 7.28 (m, 3H), 7.05 (t, 2H), 6.85 (d, 1H), 4.51 (m, 1H), 3.63 (m, 1H), 1.96 (d, 4H), 1.62 (q, 2H), 1.17 (q, 2H).

&Lt; Example 13 >

4- (4-fluorophenyl) -5- [2- (2,6-dimethylphenoxy) pyridin-4-yl]

The title compound was prepared in two steps as a 34% yield of white foam using the procedure of Example 2 (e) and 2 (f), except that 2,6-dimethylphenol was used. ES (+) MS m / e = 443 (MH ^&lt; ⁺ & gt ^; ).

&Lt; Example 14 >

4- (4-fluorophenyl) -5- [2- (4-methylphenoxy) pyridin-4-yl]

Using the procedure of Example 2 (e) and 2 (f) except 4-methylphenol was used, the title compound was prepared in two steps as a 49% yield of white foam. ES (+) MS m / e = 429 (MH ^&lt; ⁺ & gt ^; ).

&Lt; Example 15 >

4- (4-fluorophenyl) -5- [2- (4-chlorophenoxy) pyridin-4-yl]

Using the procedure of Example 2 (e) and 2 (f) except 4-chlorophenol was used, the title compound was prepared in two steps as a 46% yield of white foam. ES (+) MS m / e = 449 (MH ^&lt; ⁺ & gt ^; ).

&Lt; Example 16 >

4- (4-fluorophenyl) -5- [2- (phenoxy) pyrimidin-4-yl] imidazole

a) Preparation of 2-methylthiopyrimidine-4-carboxaldehyde-3- (N-morpholino) propylamine imine

The product of Example 1 (d) (2.75 g, 17.8 mmol) and N- (aminopropyl) morpholine (2.87 ml, 19.4 mmol), CH ₂ Cl ₂ (75 ml) and some magnesium sulfate were mixed and stirred for 16 h After stirring, the mixture was filtered and concentrated to obtain a brown oil. _{^{1 H NMR (CDCl 3):}} d 8.57 (d, 1), 8.23 (s, 1), 7.55 (d, 1), 3.73 (m, 6), 2.58 (s, 3), 2.42 (m, 6) , &Lt; / RTI &gt; 1.91 (m, 2).

b) Synthesis of 1- [3- (N-morpholino) propyl] -4- (4-fluorophenyl) -5- [2- (methylthio) pyrimidin-

The product of the previous example and the product of Example 1 (f) were reacted by the method of Example 1 (g) to give 5.3 g (72% from the product of Example 1 (d)). _{^{1 H NMR (CDCl 3):}} d 8.32 (d, 1), 7.67 (s, 1), 7.46 (m, 2), 7.04 (t, 2), 6.80 (d, 1), 4.42 (t, 2) , 3.69 (m, 4), 2.60 (s, 3), 2.38 (m, 4), 2.29 (t, 2H), 1.86 (m, 2).

c) Preparation of 1- [3- (N-morpholino) propyl] -4- (4-fluorophenyl) -5- [2- (phenoxy) pyrimidin-

The products of the previous Examples were reacted using the methods of Examples 1 (h) and 1 (i) to give the title compound as a waxy solid. mp = 95-96.

&Lt; Example 17 >

4- (4-fluorophenyl) -5- [2- (3-methoxyphenoxy) pyrimidin-4-yl]

The title compound was prepared using the methods of examples 1 (i) and 1 (j) except that 3-methoxyphenol was used. mp = 117 to 118 degrees Celsius.

&Lt; Example 18 >

4- (4-fluorophenyl) -5- [2- (4-phenylphenoxy) pyrimidin-4-yl]

The title compound was prepared using the method of Example 1 (i) and 1 (j) except 4-phenylphenol was used. mp = 192 to 193 degrees Celsius.

&Lt; Example 19 >

4- (4-fluorophenyl) -5- [2- (4-phenoxyphenoxy) pyrimidin-4-yl]

The title compound was prepared using the method of Example 1 (i) and 1 (j) except 4-phenyloxyphenol was used. mp = 174 to 175 degrees Celsius.

&Lt; Example 20 >

4- (4-fluorophenyl) -5- [2- (3-hydroxyphenoxy) pyrimidin-4- yl] imidazole

The title compound was prepared using the method of Example 1 (i) and 1 (j) except that resorcinol was used. MS ES + m / z = 431 (MH &lt; + &gt;).

&Lt; Example 21 >

4- (4-fluorophenyl) -5- [2- (4-fluorophenoxy) pyrimidin-4- yl] imidazole

The title compound was prepared using the method of Example 1 (i) and 1 (j) except 4-fluorophenol was used. MS ES + m / z = 278 (MH &lt; + &gt;).

&Lt; Example 22 >

4- (4-fluorophenyl) -5- [2- (2-hydroxyphenoxy) pyrimidin-4-yl]

The title compound was prepared using the method of Example 1 (i) and 1 (j) except that catechol was used. MS ES + m / z = 431 (MH &lt; + &gt;).

&Lt; Example 23 >

4- (4-fluorophenyl) -5- [2- (3,4-methylenedioxy) phenoxy) pyrimidin-4-yl]

The title compound was prepared using the method of Example 1 (i) and 1 (j) except that sesamol was used. mp = 131-132 degrees Celsius.

&Lt; Example 24 >

4- (4-fluorophenyl) -5- [2- (3-fluorophenoxy) pyrimidin-4-yl]

The title compound was prepared using the method of Example 1 (i) and 1 (j) except that 3-fluorophenol was used. mp = 155 degrees Celsius to 156 degrees Celsius.

&Lt; Example 25 >

4- (4-fluorophenyl) -5- [2- (2-fluorophenoxy) pyrimidin-4- yl] imidazole

The title compound was prepared using the method of Example 1 (i) and 1 (j) except 2-fluorophenol was used. mp = 154 to 155 degrees Celsius.

&Lt; Example 26 >

4- (4-fluorophenyl) -5- [2- (2-methoxyphenoxy) pyrimidin-4- yl] imidazole

The title compound was prepared using the methods of examples 1 (i) and 1 (j) except 2-methoxyphenol was used. MS ES + m / z = 446 (MH &lt; + &gt;).

&Lt; Example 27 >

4- (4-fluorophenyl) -5- [2- (3-trifluoromethylphenoxy) pyrimidin-4-yl]

The title compound was prepared using the method of Example 1 (i) and 1 (j) except that 3-trifluoromethylphenol was used. mp = 137 to 138 degrees Celsius.

&Lt; Example 28 >

4- (4-fluorophenyl) -5- [2- (3,4-difluorophenoxy) pyrimidin-4-yl]

The title compound was prepared using the method of Example 1 (i) and 1 (j) except that 3,4-difluorophenol was used. MS ES + m / z = 452 (MH &lt; + &gt;).

&Lt; Example 29 >

4- (4-fluorophenyl) -5- [2- (4-methylsulfonylphenoxy) pyrimidin-4- yl] imidazole

The title compound was prepared using the method of Example 1 (i) and 1 (j) except 4-methylsulfonylphenol was used. MS ES + m / z = 494 (MH &lt; + &gt;).

&Lt; Example 30 >

4- (4-fluorophenyl) -5- [(2-phenylthio) pyridin-4-yl]

Using the method of Example 2 (e) and 2 (f) except that thiophenol was used, the title compound was prepared in two steps to a yellow foam yield of 36%. MS ES + m / e = 431 (MH ^&lt; ⁺ & gt ^; ).

&Lt; Example 31 >

4- (4-fluorophenyl) -5- [2- (1-methyltetrazol-5-ylthio) pyridin-

The title compound was prepared in the form of a pale yellow foam using the method of Example 2 (e) and 2 (f) except that 5-mercapto-1-methyltetrazole was used. The form 60 to _{70% CH 3 CN / H 2} O and 0.1% TFA and further purified using reverse phase chromatography. The fractions were combined and made basic with 1 M sodium hydroxide and extracted three times with ethyl acetate. The combined organic layers were dried with magnesium sulfate, filtered and evaporated under reduced pressure to give a gray foam with a yield of 13%. ES (+) MS m / e = 437 (MH &lt; + &gt;).

All publications, including but not limited to patents and patent applications cited herein, are incorporated herein by reference as if each individual publication were specifically and individually incorporated by reference herein, .

The foregoing description fully discloses the present invention including its preferred embodiments. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, fully utilize the invention. Accordingly, the embodiments herein are merely exemplary and are not intended to limit the scope of the invention in any way. Exemplary embodiments of the present invention claiming exclusive rights or privileges are as follows.

Claims (38)

A compound of the following general formula I: or a pharmaceutically acceptable salt thereof. (I) In this formula, R ₁ is 4-pyridyl, pyrimidinyl, quinolyl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl, wherein the heteroaryl ring is optionally substituted with YR _a substituted, optionally C _1-4 alkyl, halogen, hydroxyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl, CH ₂ OR _12, amino, mono and di -C _{1 -6} alkyl substituted amino, or _{N (R 10) C (O} ) , and additionally substituted with independent substituents selected from R _b or NHR _a, Y is oxygen or sulfur, R ₄ is phenyl, naphth-1-yl or naphth-2-yl, or heteroaryl, optionally substituted with one or two substituents each independently selected from 4-phenyl, 4-naphthyl 1-yl, 5-naphth-2-yl or 6-naphth-2-yl in the case of substituent, halogen, cyano, _{nitro, -C (Z) NR 7 R} 17, -C (Z) oR _{16, - (CR 10 R 20} ) v COR 12, -SR 5, -SOR 5, -OR 12, halo-substituted -C _1-4 alkyl, C _1-4 alkyl, -ZC (Z) R _{12, -NR 10 C (Z) R 16} , or _{- (CR 10 R 20) v} NR 10 R 20, and, in the case of the other substitution positions, halogen, _{cyano, -C (Z) NR 13 R} 14, -C (Z) OR ₃ , - (CR ₁₀ R ₂₀ ) _m COR ₃ , -S (O) _m R ₃ , -OR ₃ , halo-substituted-C _1-4 alkyl, -C _1-4 alkyl, - _{CR 10 R 20) m "NR} 10 C (Z) R 3, -NR 10 S (O) m'R 8, -NR 10 S (O) m'NR 7 R 17, -ZC (Z) R 3 or - (CR ₁₀ R ₂₀ ) m "NR ₁₃ R ₁₄ , v is 0, or an integer of 1 or 2, m is 0, or an integer of 1 or 2, m 'is an integer of 1 or 2, m &quot; is 0, an integer of 1 to 5, R ₂ is - (C ₁₀ R ₂₀ ) _n OR ₉ , heterocyclyl, heterocyclyl C _1-10 alkyl, C _1-10 alkyl, halo substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl C _1-10 alkyl, C _5-7 cycloalkenyl, C _5-7 cycloalkenyl -C _1-10- alkyl, aryl , aryl C _1-10 alkyl, heteroaryl, heteroaryl -C _1-10 - _{alkyl, (CR 10 R 20) n} OR 11, (CR 10 R 20) n S (O) m R 18, (CR 10 R _{20) n NHS (O) 2} R 18, (CR 10 R 20) n NR 13 R 14, (CR 10 R 20) n NO 2, (CR 10 R 20) n CN, (CR 10 R 20) n ' _{SO 2 R 18, (CR 10} R 20) n S (O) m 'NR 13 R 14, (CR 10 R 20) n C (Z) R 11, (CR 10 R 20) n OC (Z) R 11 _{, (CR 10 R 20) n} C (Z) OR 11, (CR 10 R 20) n C (Z) NR 13 R 14, (CR 10 R 20) n C (Z) NR 11 OR 9, (CR 10 _{R 20) n NR 10 C (} Z) R 11, (CR 10 R 20) n NR 10 C (Z) NR 13 R 14, (CR 10 R 20) n n (OR 6) C (Z) NR 13 R _{14, (CR 10 R 20)} n n (OR 6) C (Z) R 11, (CR 10 R 20) n C (= NOR 6) R 11, (CR 10 R 20) n NR 10 C (= NR ₁₉ ) NR ₁₃ NR ₁₄ , (CR ₁₀ R ₂₀ ) _n OC (Z) NR _{13 R 14, (CR 10 R 20} ) n NR 10 C (Z) NR 13 R 14, (CR 10 R 20) n NR 10 C (Z) OR 10, 5- (R 18) -1,2,4- 3-yl or 4- (R ₁₂ ) -5- (R ₁₈ R ₁₉ ) -4,5-dihydro-1,2,4-oxadiazol-3-yl, The arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic and heterocyclic alkyl groups may be optionally substituted, n is an integer of 1 to 10, n 'is 0, an integer of 1 to 10, Z is oxygen or sulfur, R _a is aryl, aryl C _1-6 alkyl, heterocyclic, heterocyclyl C _1-6 alkyl, heteroaryl, heteroaryl C _1-6 alkyl, wherein each of these moieties may optionally be substituted, R _b is hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, aryl, arylC _1-4 alkyl, heteroaryl, heteroarylC _1-4 alkyl, heterocyclyl, or heterocyclylC _1-4 Alkyl, R ₃ is heterocyclyl, heterocyclyl C _1-10 alkyl or R ₈ , R ₅ is selected from the group consisting of hydrogen, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl or NR 8 alkyl, except for the moiety -SR ₅ is -SNR ₇ R ₁₇ and -SOR ₅ is- ₇ R &lt; ₁₇ &gt; R ₆ is selected from the group consisting of hydrogen, a pharmaceutically acceptable cation, C _1-10 alkyl, C _3-7 cycloalkyl, aryl, arylC _1-4 alkyl, heteroaryl, heteroarylC _1-4 alkyl, heterocyclic, Or C _1-10 alkanoyl, R ₇ and R ₁₇ are each independently selected from hydrogen or C _1-4 alkyl or R ₇ and R ₁₇ together with the nitrogen to which they are attached form a 5-7 membered heterocyclic ring optionally containing oxygen , Sulfur or NR &lt; _{15 &} gt ;, wherein the heteroatom R ₈ is C _1-10 alkyl, halo substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-7 cycloalkyl, C _5-7 cycloalkenyl, aryl, aryl C _1-10 alkyl, heteroaryl, heteroaryl C _{1-10 alkyl, (CR 10 R 20) n} OR 11, (CR 10 R 20) n S (O) m R 18, (CR 10 R 20) n NHS _{(O) 2 R 18, (} CR 10 R 20) NR ₁₃ R ₁₄ and _n, here, aryl, arylalkyl, heteroaryl, heteroaryl alkyl may optionally be substituted, R ₉ is hydrogen, -C (Z) R ₁₁ or optionally substituted C _1-10 alkyl, S (O) ₂ R ₁₈ , optionally substituted aryl or optionally substituted aryl-C _1-4 alkyl, R ₁₀ and R ₂₀ are each independently selected from hydrogen or C _1-4 alkyl, R ₁₁ is selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-7 cycloalkyl, heterocyclyl, heterocyclyl C _1-10 alkyl, aryl, aryl C _1-10 alkyl, heteroaryl or heteroaryl C _1-10 alkyl ego, R &lt; ₁₂ &gt; is hydrogen or R &lt; ₁₆ & R ₁₃ and R ₁₄ are each independently selected from hydrogen or optionally substituted C _1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C _1-4 alkyl, or together with the nitrogen to which they are attached form a 5-7 membered Form a heterocyclic ring, which ring optionally additionally contains a heteroatom selected from oxygen, sulfur or NR ₉ , R ₁₅ is R ₁₀ or C (Z) -C _1-4 alkyl, R ₁₆ is C _1-4 alkyl, halo-substituted -C _1-4 alkyl, or C _3-4 cycloalkyl, R ₁₈ is C _1-10 alkyl, C _3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C _1-10 alkyl, heteroaryl or heteroarylalkyl, R ₁₉ is hydrogen, cyano, C _1-4 alkyl, C _3-7 cycloalkyl or aryl. 7. The compound of claim 1, wherein R &lt; _{1 &gt;} is substituted 4-pyridyl or 4-pyrimidinyl. The method of claim 2 wherein, R _a portion of which is optionally halogen, C _1-4, halo-substituted alkyl, hydroxy, hydroxy substituted C _1-4 alkyl, C _1-4 alkoxy, S (O) _m alkyl and S (O) _m aryl (wherein m is 0, 1 or _{2), C (O) oR 11} , C (O) R 11, -OC (O) R c, -O- (CH 2) s -O, Amino, mono- and di-C _1-6 alkyl substituted amino, -N (R ₁₀ ) C (O) R _b , -C (O) NR ₁₀ R ₂₀ , cyano, nitro, as additional hetero atom selected from the enemy ₁₅ 5- to 7-membered N- heterocyclyl ring, aryl, arylalkyl, aryloxy or arylalkyloxy containing the substituted one or more times, R _b is hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, aryl, aryl C _1-4 alkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclyl or heterocyclyl C _1-4 alkyl Lt; / RTI & R _c is selected from the group consisting of C _1-6 alkyl, C _3-7 cycloalkyl, aryl, aryl C _1-4 alkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclyl, or heterocyclyl C _1-4 alkyl moieties Lt; / RTI &gt; are both optionally substituted. 4. The compound of claim 3 wherein the substituent is selected from the group consisting of hydrogen, halosubstituted alkyl, hydroxy, cyano, alkyl, aryl, alkoxy, aryloxy, arylalkyloxy, alkylthio, alkylsulfonyl, aminocarbonyl, methylenedioxy, tetra Sol, methyltetazolyl. 3. The compound of claim 2 wherein R &lt; ₄ &gt; is optionally substituted phenyl. The method of claim 5, wherein the phenyl is _{halogen, -SR 5, S (O)} R 5, -OR 12, halo-substituted compounds independently substituted one or more times with -C _1-4 alkyl, or C _1-4 alkyl . The compound of claim 1, wherein R ₂ is selected from optionally substituted C _1-10 alkyl, optionally substituted heterocyclyl, optionally substituted heterocyclyl C _1-10 alkyl, optionally substituted C _3-7 cycloalkyl, a C _3-7 compound is selected from cycloalkyl C _1-10 alkyl. 8. Compounds according to claim 7, wherein R &lt; _{2 &gt;} is optionally substituted heterocyclyl, or optionally substituted heterocyclylC _1-10 alkyl. The method of claim 8, wherein the substituents are halogen, C _1-4 alkyl, _{aryl, C (O) OR 11,} C (O) H, C (O) C 1-4 alkyl, hydroxy substituted C _1-10 alkyl, , C _1-10 alkoxy, S (O) _m C _1-4 alkyl (wherein m is 0, 1 or 2), or NR ₁₀ R ₂₀ . 9. A compound according to claim 8 wherein R &lt; _{2 &gt;} is selected from the group consisting of morpholino propyl, piperidine, N-methylpiperidine, N-benzylpiperidine, 2,2,6,6-tetramethylpiperidine, Piperidine, or 4-amino-2,2,6,6-tetramethylpiperidine. 8. Compounds according to claim 7, wherein R &lt; _{2 &gt;} is optionally substituted C _3-7 cycloalkyl, or optionally substituted C _3-7 cycloalkylC _1-10 alkyl. 12. The method of claim 11, wherein the optional substituents of halogen, hydroxy, C _1-10 alkoxy, S (O) _m-alkyl (wherein, m is 0, 1 or 2), S (O) _m aryl, cyano, nitro, NR ₇ R _{17 group, N (R 10) C (} O) , and, X ₁ is C _1-4 alkyl, aryl or aryl C _{1-4 alkyl, N (R 10) C (} O) aryl, C _{1 -10} alkyl, optionally substituted alkyl (substituents are halogen, hydroxy, nitro, cyano, NR ₇ R ₁₇ group, S (O) _m alkyl and S (O) _m aryl), optionally substituted alkylene, optionally (O) OR ₁₁ , R _e group, -C (O) H, ═O, ═N-OR ₁₁ , -N (H) -OH (or alkyl substituted at the nitrogen or oxime moiety, or (OR _d ) -C (O) -R _f , optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heterocyclyl or heterocyclic C _1-4 alkyl , &Lt; / RTI &gt; R _d is hydrogen, a pharmaceutically acceptable cation, aroyl or C _1-10 alkanoyl; R _e is a 1,3-dioxyalkylene group of the general formula -O- (CH ₂ ) _s -O- wherein s is 1 to 3, R _f is NR ₂₁ R ₂₂ , alkyl _1-6 , halo substituted alkyl _1-6 , hydroxy substituted alkyl _1-6 , alkenyl _2-6 , halogen, alkyl _1-6 , halo substituted alkyl _1-6 , Hydroxyl, or heteroaryl or aryl optionally substituted with alkoxy _1-6 , R &lt; ₂₁ &gt; is hydrogen or alkyl _1-6 , R ₂₂ is selected from the group consisting of hydrogen, alkyl _1-6 , aryl, benzyl, heteroaryl, alkyl substituted by halogen or hydroxyl, or halo, cyano, alkyl _1-12 , alkoxy _1-6 , halo substituted alkyl _1-6 , Alkylthio, alkylsulfonyl, or alkylsulfinyl, or R ₂₁ and R ₂₂ together with the nitrogen to which they are attached form a 5 to 7 membered ring, Is optionally substituted by a heteroatom selected from oxygen, sulfur or nitrogen. 12. The compound of claim 11, wherein R ₂ is selected from the group consisting of hydroxycyclohexyl, 4-methyl-4-hydroxycyclohexyl, 4-pyrrolidinyl-cyclohexyl, Acetamidocyclohexyl, 4-ketocyclohexyl, 4-oxiranyl, or 4-hydroxy-4- (1-propynyl) cyclohexyl. The method according to claim 1, 4- (4-fluorophenyl) -5- (2-phenoxypyrimidin-4-yl) imidazole 4- (4-fluorophenyl) -5- (2-phenoxy-4-pyridinyl) imidazole 4- (4-fluorophenyl) -5- [2- (4-methoxyphenoxy) -4-pyridinyl] imidazole 4- (4-fluorophenyl) -5- [2- (4-fluorophenoxy) -4-pyridinyl] imidazole 4- (4-fluorophenyl) -5- [2- (4-methoxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-fluorophenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-aminocarbonylphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-ethylphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-benzyloxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-cyanophenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-hydroxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5- [2- (phenoxy) pyrimidin- 4- (4-fluorophenyl) -5- [2- (2,6-dimethylphenoxy) pyridin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-methylphenoxy) pyridin-4-yl] 4- (4-fluorophenyl) -5- [2- (4-chlorophenoxy) pyridin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (phenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (3-methoxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-phenylphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-phenoxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (3-hydroxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-fluorophenoxy) pyrimidin-4- yl] imidazole 4- (4-fluorophenyl) -5- [2- (2-hydroxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2 - ((3,4-methylenedioxy) phenoxy) pyrimidin- 4- (4-fluorophenyl) -5- [2- (3-fluorophenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (2-fluorophenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (2-methoxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (3-trifluoromethylphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (3,4-difluorophenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-methylsulfonylphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- (2-thiophenoxypyrimidin-4-yl) -imidazole 4- (4-fluorophenyl) -5- [2- (1-methyltetrazol-5-ylthio) pyridin- Or a pharmaceutically acceptable salt thereof. 15. A pharmaceutical composition comprising a compound of any one of claims 1 to 14 and a pharmaceutically acceptable carrier or diluent. 15. A method for the treatment of a cytokine mediated disease in a mammal comprising administering to a mammal in need of treatment of a cytokine mediated disease an effective amount of a compound of general formula I according to any one of claims 1 to 14. 18. The method of claim 16 wherein the mammal is selected from the group consisting of psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other joint diseases, sepsis, Inflammatory bowel disease, acute respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, cirrhosis, sarcoisosis, osteoporosis, osteoporosis, osteoporosis, osteoporosis, Atherosclerosis, restenosis, reperfusion injury of the heart and kidney, thrombosis, renal tubular nephritis, diabetes, host response to transplantation, rejection of other transplantation, inflammatory bowel disease, Crohn's disease , A disease associated with a cytokine-mediated disease selected from ulcerative colitis, multiple sclerosis, chronic degeneration, eczema, contact dermatitis, psoriasis, sunburn, and conjunctivitis Methods of treatment of water. 17. The method of claim 16, wherein the disease state is mediated by IL-1, IL-6, IL-8, or TNF. 17. The method of claim 16, wherein the cytokine mediated disease state is asthma, osteoporosis, or arthritis. 15. A method of treating inflammation in a mammal comprising administering to a mammal in need of treatment an inflammation an effective amount of a compound of formula I according to any one of claims 1 to 14. 15. A method for the treatment of osteoporosis in a mammal comprising administering to a mammal in need of treatment an effective amount of a compound of general formula I according to any one of claims 1 to 14 for the treatment of osteoporosis. Comprising administering an effective amount of a compound of general formula I according to any one of claims 1 to 14 to a mammal in need of inhibition of the synthesis of prostaglandin endoperoxide synthase-2 (PGHS-2) A method for inhibiting the synthesis of prostaglandin endoperoxidase synthase-2 (PGHS-2) in mammals. 23. The method of claim 22, wherein the inhibition of PGHS-2 is used for the prevention and treatment of edema, fever, algesia, neuromuscular pain, headache, cancer pain or joint pain. A method of treating a CSBP / RK / p38 kinase mediated disease in a mammal, comprising administering an effective amount of a compound of formula I of claim 1 to a mammal in need of treatment of a CSBP / RK / p38 kinase mediated disease. 25. The method of claim 24, wherein said mammal is selected from the group consisting of psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other joint diseases, sepsis, , Septic shock, gram negative sepsis, toxic shock, Alzheimer's disease, seizures, nerve trauma, asthma, adult respiratory distress syndrome, brain malaria, chronic pulmonary inflammatory disease, cirrhosis, sarcoisosis, Crohn's syndrome, Crohn's disease, Crohn's disease, diabetic nephropathy, diabetic nephropathy, diabetic nephropathy, diabetic nephropathy, renal insufficiency, restenosis, cardiac and renal reperfusion injury, thrombosis, A method of treating a CSBP / RK / p38 kinase mediated disease which is a disease, ulcerative colitis, multiple sclerosis, chronic degeneration, eczema, contact dermatitis, psoriasis, sunburn, and conjunctivitis. 26. The compound of claim 25, wherein the compound is 4- (4-fluorophenyl) -5- (2-phenoxypyrimidin-4-yl) imidazole 4- (4-fluorophenyl) -5- (2-phenoxy-4-pyridinyl) imidazole 4- (4-fluorophenyl) -5- [2- (4-methoxyphenoxy) -4-pyridinyl] imidazole 4- (4-fluorophenyl) -5- [2- (4-fluorophenoxy) -4-pyridinyl] imidazole 4- (4-fluorophenyl) -5- [2- (4-methoxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-fluorophenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-aminocarbonylphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-ethylphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-benzyloxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-cyanophenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-hydroxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5- [2- (phenoxy) pyrimidin- 4- (4-fluorophenyl) -5- [2- (2,6-dimethylphenoxy) pyridin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-methylphenoxy) pyridin-4-yl] 4- (4-fluorophenyl) -5- [2- (4-chlorophenoxy) pyridin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (phenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (3-methoxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-phenylphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-phenoxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (3-hydroxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-fluorophenoxy) pyrimidin-4- yl] imidazole 4- (4-fluorophenyl) -5- [2- (2-hydroxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2 - ((3,4-methylenedioxy) phenoxy) pyrimidin- 4- (4-fluorophenyl) -5- [2- (3-fluorophenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (2-fluorophenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (2-methoxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (3-trifluoromethylphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (3,4-difluorophenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-methylsulfonylphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- (2-thiophenoxypyrimidin-4-yl) -imidazole 4- (4-fluorophenyl) -5- [2- (1-methyltetrazol-5-ylthio) pyridin- Or a pharmaceutically acceptable salt thereof. Compounds of formula II &Lt; With a compound of formula III (III) And Formula II of the isonitrile when reacted with sufficient strong base on to dehydrogenation a part and subsequently required claim 1 general, comprising the conversion of R _1, R _2, and the precursor of the R ₄ group a group R _1, R ₂ and R ₄ 0.0 &gt; I &lt; / RTI &gt; Wherein p is 0 or 2, R ₁ , R ₂ and R ₄ are as defined in claim ₁ or are precursors of the R ₁ , R ₂ and R ₄ groups and Ar is an optionally substituted phenyl group. 28. The method of claim 27 wherein TBD is used as the base when the reaction is p = 0. 28. The method of claim 27 wherein an amine, carbonate, hydrate, or alkyl or aryl lithium reagent is used as the base when the reaction is p = 2. 28. The method of claim 27, wherein the imine of formula III is isolated prior to reaction with the compound of formula II. 31. The method of claim 30, wherein the imine of formula III is formed in situ prior to reaction with the compound of formula II. 32. The process of claim 31, wherein the aldehyde of the formula R ₁ CHO wherein R ₁ is as defined in formula I is reacted with a compound of the formula R ₂ NH ₂ wherein R ₂ is as defined in formula I, &Lt; / RTI &gt; in the presence of a primary amine. 33. The method of claim 32, wherein the imine is formed in situ using dehydration conditions. 34. The method of claim 33, wherein the solvent is N, N-dimethyl-formamide (DMF), halogenated solvent, tetrahydrofuran (THF), dimethylsulfoxide (DMSO), alcohol, benzene or toluene or DME. 33. The method of claim 32 wherein the aldehyde R ₁ CHO to produce a compound of formula I or a pharmaceutically acceptable salt thereof is a pyrimidine aldehyde of the formula: In the formula, X is YR &_lt; _a &_gt;, and X &lt; ₁ &gt; is as defined for a group optionally substituted in the R &lt; ₁ &gt; 33. The method of claim 32, wherein the aldehyde R ₁ CHO to produce a compound of formula I, or a pharmaceutically acceptable salt thereof, is pyridine aldehyde of the formula: In the formula, X is YR &_lt; _a &_gt;, and X &lt; ₁ &gt; is as defined for a group optionally substituted in the R &lt; ₁ &gt; According to claim 32, wherein the primary amine R ₂ NH ₂ R is R ₂ is piperidine, 1-Formyl-4-piperidine, 1-benzyl-4-piperidine, 1-methyl-4-P Piperidine, morpholino propyl, pyrrolidinine propyl, or a derivative thereof, or a salt thereof. Piperidinyl &lt; / RTI &gt; propyl. 28. The compound of claim 27, wherein the compound is 4- (4-fluorophenyl) -5- (2-phenoxypyrimidin-4-yl) imidazole 4- (4-fluorophenyl) -5- (2-phenoxy-4-pyridinyl) imidazole 4- (4-fluorophenyl) -5- [2- (4-methoxyphenoxy) -4-pyridinyl] imidazole 4- (4-fluorophenyl) -5- [2- (4-fluorophenoxy) -4-pyridinyl] imidazole 4- (4-fluorophenyl) -5- [2- (4-methoxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-fluorophenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-aminocarbonylphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-ethylphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-benzyloxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-cyanophenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-hydroxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-hydroxycyclohexyl) -4- (4-fluorophenyl) -5- [2- (phenoxy) pyrimidin- 4- (4-fluorophenyl) -5- [2- (2,6-dimethylphenoxy) pyridin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-methylphenoxy) pyridin-4-yl] 4- (4-fluorophenyl) -5- [2- (4-chlorophenoxy) pyridin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (phenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (3-methoxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-phenylphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-phenoxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (3-hydroxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-fluorophenoxy) pyrimidin-4- yl] imidazole 4- (4-fluorophenyl) -5- [2- (2-hydroxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2 - ((3,4-methylenedioxy) phenoxy) pyrimidin- 4- (4-fluorophenyl) -5- [2- (3-fluorophenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (2-fluorophenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (2-methoxyphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (3-trifluoromethylphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (3,4-difluorophenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- [2- (4-methylsulfonylphenoxy) pyrimidin-4-yl] -imidazole 4- (4-fluorophenyl) -5- (2-thiophenoxypyrimidin-4-yl) -imidazole 4- (4-fluorophenyl) -5- [2- (1-methyltetrazol-5-ylthio) pyridin- &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.